JP7836361B2 - Methods for stabilizing Parkinson's disease medications - Google Patents

Description

This invention relates to a pharmaceutical composition containing istradefylline, a method for stabilizing istradefylline, and the like.

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

It is known that it is not easy to formulate solid dosage forms of diarylvinylene compounds such as istradefylline that have excellent formulation properties (e.g., hardness, disintegration, dissolution, stability, etc.). It has been reported that solid dosage forms with a general composition, such as those described in Japanese Patent Application Publication No. 6-211856 (Patent Document 1), have problems such as (a) insufficient hardness, (b) long disintegration time, (c) a tendency for delayed dissolution, and (d) poor stability (Patent Documents 2 and 3).
Among these challenges, regarding photostability, it has been reported that the generation of photodegradation products of istradefylline can be suppressed by i) including crystalline cellulose in the solid dosage form (Patent Document 2), or ii) coating the solid dosage form with a coating composition containing iron oxide (Patent Document 3). However, in case ii), coating increases the number of steps, which requires time and labor, thus increasing costs. In addition, in tablets that require splitting, problems such as the score line being filled in by the coating are likely to occur, and after splitting, the split surface is exposed, so the photostability effect cannot be expected, which is a disadvantage (Patent Document 4).

On the other hand, Parkinson's disease patients are predominantly elderly and often experience dysphagia (difficulty swallowing). To prevent aspiration of tablets due to dysphagia, methods such as mixing tablets with medication jelly or crushing tablets and mixing them with food are employed. Orally disintegrating tablets (OD tablets) are also useful for elderly patients with dysphagia.
Considering these circumstances, there is a need for the development of istradefylline preparations that can improve medication adherence among Parkinson's disease patients and simplify prescribing for healthcare professionals.

Japanese Patent Application Publication No. 6-211856 Patent No. 4673745 Patent No. 4413866 Patent No. 4214128

One of the objectives of the present invention is to provide a pharmaceutical composition containing istradefylline in which the photodegradation of istradefylline in the pharmaceutical composition is suppressed. Another objective of the present invention is to provide a method for stabilizing istradefylline.
The inventors investigated pharmaceutical compositions that suppress the photodegradation of istradefylline and found that mixing istradefylline with a coloring agent can suppress the photodegradation of istradefylline in a pharmaceutical composition. They also found that the photodegradation of istradefylline is accelerated when it is subjected to tablet compression pressure. Based on these findings, the present invention was completed.

In one aspect, the present invention provides a pharmaceutical composition comprising a mixture of istradefylline and a coloring agent.

In one aspect, the present invention provides a pharmaceutical composition comprising a mixture of istradefylline and a tablet pressure-relieving substance.

In one aspect, the present invention provides a method for stabilizing istradefylline, comprising the step of preparing a mixture of istradefylline and a coloring agent.

In one aspect, the present invention provides a method for stabilizing istradefylline, comprising the step of preparing a mixture of istradefylline and a tablet pressure-relieving substance.

In one aspect, the present invention provides a method for producing a pharmaceutical composition containing istradefylline.

In one aspect, the present invention provides a pharmaceutical composition that contains istradefylline having an average particle size of more than 20 μm and does not contain crystalline cellulose.
In one aspect, the present invention provides a pharmaceutical composition comprising a mixture of istradefylline and a lubricant.
In one aspect, the present invention provides a method for stabilizing istradefylline, comprising the step of preparing a mixture of istradefylline and a lubricant.

Figure 1 shows the formulations of the tablets for Examples 1 to 7 and their stability test results. It also shows the hardness and in-oral disintegration time for the tablets of Examples 4 and 7. The unit of each component's content is mg. Stability tests for Examples 1 and 2 were conducted by irradiating with 4000 lux of light for two weeks, while stability tests for Examples 3 to 7 were conducted by irradiating with 1,200,000 lux/hr of light. HPC-L: Hydroxypropylcellulose, manufactured by Nippon Soda Co., Ltd. PVA/PEG graft copolymer: Polyvinyl alcohol/polyethylene glycol graft copolymer, CoriCoat IR, BASF Japan Ltd. PEG6000P: Polyethylene glycol 6000P, Sanyo Chemical Industries, Ltd. FC Department: Film Coating Department Figure 2 shows the formulations, stability test results, hardness, and disintegration times of the tablets of Example 4 and Example 7. The formulations, stability test results, hardness, and disintegration times of the tablets of Example 1 and Comparative Examples 1-3 of Japanese Patent Publication No. 4673745 are also described. The disintegration times for Example 4 and Example 7 represent the disintegration time in the human oral cavity, while the disintegration times for Example 1 and Comparative Examples 1-2 of Japanese Patent Publication No. 4673745 represent the disintegration times according to the method used in the disintegration test described in the Revised First Section of the Fourteenth Edition of the Japanese Pharmacopoeia. Figure 3 shows the formulations and stability test results of the tablets for Examples 3 to 7. Stability tests were conducted both before crushing and, for the tablets in Examples 4 to 7, after crushing, and the results are shown in Figure 3. In addition, for Examples 4 and 7, stability tests were also conducted on the granules (whole granules) before tableting, and the results are shown in Figure 3. Figure 4 shows the inhibitory effect of magnesium stearate on the formation of photodegradable products of istradefylline. Istradephylline-containing tablets prepared using lactose monohydrate as an excipient were irradiated with light, and the amount of photodegradable products (dimers) in the tablets was evaluated. Figure 5 shows the inhibitory effect of magnesium stearate on the formation of photodegradation products of istradefylline. Istradephylline-containing tablets prepared using D-mannitol as an excipient were irradiated with light, and the amount of photodegradation products (dimers) in the tablets was evaluated. Figure 6 shows the inhibitory effect of calcium stearate on the formation of photodegradable products of istradefylline. Istradephylline-containing tablets prepared using lactose monohydrate as an excipient were irradiated with light, and the amount of photodegradable products (dimers) in the tablets was evaluated. Figure 7 shows the effect of calcium stearate on the suppression of photodegradation product formation of istradefylline. Istradephylline-containing tablets prepared using D-mannitol as an excipient were irradiated with light, and the amount of photodegradation product (dimer) in the tablets was evaluated. Figure 8 shows the effect of sodium stearyl fumarate on the suppression of photodegradation product formation of istradefylline. Istradephylline-containing tablets prepared using D-mannitol as an excipient were irradiated with light, and the amount of photodegradation product (dimer) in the tablets was evaluated. Figure 9 shows the effect of tablet compression pressure on the formation of photodegradable products of istradefylline. It was shown that in tablets containing D-mannitol and magnesium stearate, the formation of dimers could be suppressed to less than 0.5% by weight by using a tablet compression pressure of 10 kN or less. Figure 10 shows the effect of tablet compression pressure on the photodegradation product formation of istradefylline. It was shown that even with a tablet compression pressure of 30 kN, the formation of dimers could be suppressed to less than 0.5% by weight in tablets containing D-mannitol and yellow ferric oxide.

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

The colorants that can be used in the pharmaceutical compositions provided by the present invention are not particularly limited, but examples include iron oxide, yellow iron oxide, yellow ferric oxide, brown iron oxide, ferric oxide, Food Yellow No. 4, Food Yellow No. 5, Food Yellow No. 4 aluminum lake, Food Yellow No. 5 aluminum lake, Food Red No. 2, Food Red No. 3, Food Red No. 102, red iron oxide, black iron oxide, carmine-P, riboflavin, carbon black, medicinal charcoal, etc. Preferably, iron oxide, yellow ferric oxide, or ferric oxide. Two or more colorants may be used in the pharmaceutical compositions provided by the present invention. The colorants are preferably contained in the pharmaceutical composition in an amount of 0.001 to 10.0% by weight, more preferably in an amount of 0.005 to 5.0% by weight, and even more preferably in an amount of 0.01 to 5.0% by weight.
In one embodiment, the coloring agent is mixed with istradefylline and included in the pharmaceutical composition provided by the present invention (for example, a solid dosage form (e.g., a tablet)). For example, the pharmaceutical composition provided by the present invention is a tablet containing a mixture of istradefylline and a coloring agent, and the mixture of istradefylline and a coloring agent may be a granule. The mixture of istradefylline and a coloring agent (e.g., a granule) may be included in the uncoated portion of the tablet. The weight ratio of istradefylline to the coloring agent in the mixture can be appropriately set by those skilled in the art, for example, the weight of the coloring agent may be 0.001 to 1, preferably 0.05 to 0.5, of the weight of istradefylline. The granule may be prepared by methods commonly used in the art, for example, by wet granulation, dry granulation, etc.
In one embodiment, a composition containing a coloring agent can be used as an inhibitor of istradefylline photodegradation.

Examples of tableting pressure-relieving substances that can be used in the pharmaceutical compositions provided by the present invention include low-melting-point oily substances, lubricating substances, and substances with high porosity and a high degree of freedom of pressure deformation. More specific examples of tableting pressure-relieving substances that can be used in the pharmaceutical compositions provided by the present invention include lactose monohydrate, mannitol, partially pregelatinized starch, crystalline cellulose, light anhydrous silicic acid, anhydrous calcium hydrogen phosphate, magnesium aluminometasilicate, stearic acid, calcium stearate, magnesium stearate, sodium stearyl fumarate, sucrose fatty acid esters, hydrogenated oil, carnauba wax, glycerin fatty acid esters, triethyl citrate, triacetin, diethyl sebacate, dibutyl sebacate, castor oil, and polyethylene glycol. While there is no intention to be bound by any particular theory, low-melting-point oily substances can avoid damage to the crystals of active pharmaceutical ingredients (APIs) during tableting by softening under pressure, lubricating substances by reducing friction between particles during tableting, and substances with high porosity and a high degree of freedom of pressure deformation by deforming to fill the gaps between particles during tableting. Each of these characteristics can help avoid damage to the crystals of APIs.
In this specification, low-melting-point oily substances are those that exhibit an oily or greasy state and typically have a melting point of about 20 to 90°C. Examples include hydrocarbons, higher fatty acids, higher alcohols, fatty acid esters of polyhydric alcohols, higher alcohol ethers of polyhydric alcohols, polymers or copolymers of alkylene oxides, and more specifically, stearic acid, calcium stearate, magnesium stearate, sucrose fatty acid esters, hydrogenated oils, carnauba wax, glycerin fatty acid esters, triethyl citrate, triacetin, diethyl sebacate, dibutyl sebacate, castor oil, and polyethylene glycol.
In this specification, a lubricating substance can be a substance used as a lubricant in the pharmaceutical field, and examples include light anhydrous silicic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, hydrogenated oil, magnesium aluminometasilicate, and the like.
Examples of materials with high porosity and a high degree of freedom in pressure deformation include additives manufactured in bulk by granulation or spray drying (e.g., lactose monohydrate, mannitol, anhydrous calcium hydrogen phosphate, etc.).
Two or more tableting pressure-relieving substances may be used in the pharmaceutical composition provided by the present invention. The tableting pressure-relieving substances may be contained in the pharmaceutical composition in an amount ranging from 0.1 to 98% by weight. For example, they may be contained in amounts of 0.1 to 70% by weight, 10 to 70% by weight, 30 to 60% by weight, 0.1 to 5% by weight, 0.1 to 2% by weight, 0.3 to 5% by weight, 0.3 to 2% by weight, 0.5 to 5% by weight, and 0.5 to 2% by weight.
In one embodiment, the tableting pressure-relieving substance is mixed with istradefylline and included in the pharmaceutical composition provided by the present invention (e.g., a solid dosage form (e.g., a tablet)). For example, the pharmaceutical composition provided by the present invention is a tablet containing a mixture of istradefylline and the tableting pressure-relieving substance, and the mixture containing istradefylline and the tableting pressure-relieving substance may be a granule. The mixture containing istradefylline and the tableting pressure-relieving substance (e.g., a granule) may be included in the uncoated portion of the tablet. The weight ratio of istradefylline to the tableting pressure-relieving substance in the mixture can be appropriately set by those skilled in the art, for example, the weight of the tableting pressure-relieving substance may be 0.001 to 10, preferably 1 to 5, of the weight of istradefylline. The granules may be prepared by methods commonly used in the art, for example, by wet granulation, dry granulation, etc.
In one embodiment, a composition containing a tablet pressure-relieving substance can be used as an inhibitor of istradefylline photodegradation.

The pharmaceutical compositions provided by the present invention may be solid formulations, such as fine granules, granules, tablets, capsules, and dry syrups. Preferably, they are tablets (e.g., film-coated tablets, uncoated tablets), and more preferably, orally disintegrating tablets (e.g., uncoated orally disintegrating tablets, film-coated orally disintegrating tablets).
When the pharmaceutical composition provided by the present invention is an orally disintegrating tablet, the preferred disintegration time is within 180 seconds (for example, 10 to 180 seconds), more preferably within 60 seconds (for example, 10 to 60 seconds), and even more preferably within 30 seconds (for example, 10 to 30 seconds). The method for measuring the disintegration time is not particularly limited, but for example, it can be measured using a disintegration tester in accordance with the disintegration test method specified in the 17th edition of the Japanese Pharmacopoeia.
When the pharmaceutical composition provided by the present invention is a tablet (for example, an orally disintegrating tablet), its hardness may be 20 N or more, and for example, 20 N to 150 N, 20 N to 100 N, 20 N to 50 N, 25 N to 150 N, 25 N to 100 N, 25 N to 50 N, 50 N to 150 N, 50 N to 100 N, 60 N or more (for example, 60 to 100 N), 65 N or more (for example, 65 to 100 N), or 70 N or more (for example, 70 to 100 N).
The pharmaceutical composition provided by the present invention may be used in the treatment of Parkinson's disease.

The pharmaceutical compositions provided by the present invention may contain additives commonly used in the pharmaceutical technology field. Examples of such additives include excipients, binders, disintegrants, fluidizers, sweeteners, lubricants, pH adjusters, surfactants, and fragrances.

Examples of excipients that can be used in the pharmaceutical compositions provided by the present invention include sugars such as lactose (e.g., lactose monohydrate, anhydrous lactose), glucose, sucrose, fructose, and maltose; sugar alcohols such as erythritol, sorbitol, maltitol, xylitol, and D-mannitol; starch (e.g., corn starch, potato starch, rice starch, wheat starch, partially pregelatinized starch); crystalline cellulose; magnesium aluminometasilicate; anhydrous calcium phosphate; anhydrous calcium hydrogen phosphate; precipitated calcium carbonate; calcium silicate; calcium lactate; and ethylcellulose. Examples of preferred excipients used in the pharmaceutical compositions provided by the present invention include D-mannitol, anhydrous calcium hydrogen phosphate, and combinations thereof.
The excipient content in the pharmaceutical composition provided by the present invention may be 20 to 95% by weight, preferably 30 to 90% by weight, and more preferably 30 to 85% by weight, relative to the pharmaceutical composition.
In one embodiment, the excipient used in the pharmaceutical composition provided by the present invention is D-mannitol, which is typically used in accordance with the Japanese, European, and American pharmacopoeias. The crystalline form, particle size, and specific surface area of D-mannitol are not particularly limited, but the crystalline form may be α-type, β-type, δ-type, or amorphous; the particle size is preferably 10 μm to 250 μm, more preferably 20 μm to 150 μm; the specific surface area is preferably 0.1 ^m² /g to 5 ^m² /g, more preferably 0.1 ^m² /g to 4 ^m² /g, and even more preferably 2 ^m² /g to 3.5 ^m² /g.
Furthermore, the melting point of D-mannitol usable in the pharmaceutical composition provided by the present invention is between 166 and 169°C, and the loss on drying (105°C, 4 hours) is 0.5% or less. In addition, the conductivity at 25°C when 20g is dissolved in 100ml may be 20 μS· ^cm⁻¹ .
Crystal form, particle size, and specific surface area can be measured by well-known methods, such as X-ray diffraction, laser diffraction particle size measurement, and BET specific surface area measurement (multi-point method).
Two or more types of D-mannitol with different properties such as particle size may be used in the pharmaceutical composition provided by the present invention. Granulated or spray-dried D-mannitol may also be used in the pharmaceutical composition provided by the present invention. D-mannitol is preferably contained in the pharmaceutical composition in an amount of 1 to 98% by weight, more preferably in an amount of 10 to 70% by weight, and even more preferably in an amount of 25 to 60% by weight.
D-mannitol may be mixed with istradefylline and included in the pharmaceutical composition provided by the present invention (for example, a solid dosage form (e.g., a tablet)). In one embodiment, the pharmaceutical composition provided by the present invention is a tablet containing a mixture of istradefylline and D-mannitol, where the mixture of istradefylline and D-mannitol may be a granule. The mixture of istradefylline and D-mannitol (e.g., a granule) may be included in the uncoated portion of the tablet. The weight ratio of istradefylline to D-mannitol in the mixture can be appropriately set by those skilled in the art, for example, the weight of D-mannitol may be 1 to 10, preferably 1 to 5, of the weight of istradefylline. The granule may be prepared by methods commonly used in the art, for example, by wet granulation, dry granulation, etc.
In one embodiment, the excipient used in the pharmaceutical composition provided by the present invention is anhydrous calcium hydrogen phosphate, which is typically used if it conforms to the Japanese, European, and American pharmacopoeias. Commercially available anhydrous calcium hydrogen phosphate can be used. Its specific surface area is not particularly limited, but is preferably 0.1 ^m² /g or more and 30 ^m² /g or less, more preferably 0.5 ^m² /g or more and 20 ^m² /g or less, and even more preferably 0.5 ^m² /g or more and 3 ^m² /g or less. Furthermore, the loss on ignition (1g, 800-825°C) may be between 6.6% and 8.5%.
The specific surface area can be measured by well-known methods, for example, by the BET specific surface area measurement method (multi-point method).
Two or more types of anhydrous calcium hydrogen phosphate with different properties such as specific surface area may be used in the pharmaceutical composition provided by the present invention. Granulated or spray-dried anhydrous calcium hydrogen phosphate may also be used in the pharmaceutical composition provided by the present invention. The anhydrous calcium hydrogen phosphate is preferably contained in the pharmaceutical composition in an amount of 1 to 98% by weight, more preferably in an amount of 3 to 30% by weight, and even more preferably in an amount of 5 to 15% by weight.
Anhydrous calcium hydrogen phosphate may be mixed with istradefylline and included in the pharmaceutical composition provided by the present invention (for example, a solid dosage form (e.g., a tablet)). In one embodiment, the pharmaceutical composition provided by the present invention is a tablet containing a mixture of istradefylline and anhydrous calcium hydrogen phosphate, and the mixture of istradefylline and anhydrous calcium hydrogen phosphate may be a granule. The mixture of istradefylline and anhydrous calcium hydrogen phosphate (e.g., a granule) may be included in the uncoated portion of the tablet. The weight ratio of istradefylline to anhydrous calcium hydrogen phosphate in the mixture can be appropriately set by those skilled in the art, for example, the weight of anhydrous calcium hydrogen phosphate may be 0.03 to 3, preferably 0.1 to 1, of the weight of istradefylline. The granule may be prepared by methods commonly used in the art, for example, by wet granulation, dry granulation, etc.

Examples of binders that can be used in the pharmaceutical compositions provided by the present invention include hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, dextrin, methylcellulose, polyvinyl alcohol, sodium alginate, aminoalkyl methacrylate copolymer, polyethylene glycol, pregelatinized starch, agar, and gelatin. A preferred example of a binder used in the pharmaceutical compositions provided by the present invention is hydroxypropyl cellulose.
The binder content in the pharmaceutical composition provided by the present invention may be 0.1 to 30% by weight, preferably 0.3 to 10% by weight, and more preferably 1 to 5% by weight, relative to the pharmaceutical composition.

Examples of disintegrants that can be used in the pharmaceutical compositions provided by the present invention include sodium alginate, sodium starch glycolate, croscarmellose sodium, carmellose calcium, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospovidone, and carmellose. A preferred example of a disintegrant used in the pharmaceutical compositions provided by the present invention is crospovidone.
The content of the disintegrant in the pharmaceutical composition provided by the present invention may be 0.3 to 20% by weight, preferably 1 to 10% by weight, and more preferably 3 to 5% by weight, relative to the pharmaceutical composition.

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

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

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

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

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

Examples of fragrances that can be used in the pharmaceutical compositions provided by this invention include citrus fragrances such as lemon, orange, and grapefruit, as well as peppermint, spearmint, and menthol.

The pharmaceutical composition provided by the present invention may further contain inorganic substances that are expected to have a stabilizing effect on istradefylline. Examples of such inorganic substances include titanium dioxide, zinc oxide, magnesium oxide, talc, magnesium silicate, synthetic aluminum silicate, magnesium carbonate, calcium sulfate, aluminum sulfate, and barium sulfate. Preferred examples of inorganic substances used in the pharmaceutical composition provided by the present invention include titanium dioxide and talc. The content of inorganic substances in the pharmaceutical composition provided by the present invention can be appropriately set by those skilled in the art. For example, it may be 0.01 to 10% by weight, preferably 0.05 to 3% by weight, and more preferably 0.1 to 1% by weight, relative to the pharmaceutical composition.

In the pharmaceutical compositions provided by the present invention, istradefylline, granules containing istradefylline, and uncoated tablets may each be coated. The content of the coating layer can be appropriately determined by those skilled in the art, but for example, it may be 0.01 to 10% by weight relative to the pharmaceutical composition. In addition to the coating base, the coating layer may appropriately contain plasticizers, colorants, inorganic substances expected to have a stabilizing effect on istradefylline, glossing agents, etc.
Examples of coating bases include hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethylcellulose, cellulose acetate phthalate, methacrylic acid copolymer, polyvinylpyrrolidone, and polyvinyl alcohol-polyethylene glycol graft copolymer, with hydroxypropyl methylcellulose and polyvinyl alcohol-polyethylene glycol graft copolymer being particularly preferred. The content of the coating base in the pharmaceutical composition provided by the present invention may be 0.01 to 10% by weight, preferably 0.3 to 3% by weight, relative to the pharmaceutical composition.
Examples of plasticizers that can be used for coating include triethyl citrate, medium-chain triglyceride, triacetin, glycerin, propylene glycol, and polyethylene glycol (e.g., macrogol 6000), with polyethylene glycol being particularly preferred. The content of the plasticizer used for coating may be 0.01 to 1% by weight, preferably 0.03 to 3% by weight, relative to the pharmaceutical composition.
As a coloring agent that can be used for coating, any coloring agent that can be used in the pharmaceutical composition provided by the present invention as described above can be used as appropriate. Examples of preferred coloring agents that can be used for coating include iron oxide, ferric oxide, and yellow ferric oxide. The content of the coloring agent used for coating may be 0.001 to 1% by weight, preferably 0.01 to 0.1% by weight, relative to the pharmaceutical composition.
Examples of glossing agents that can be used in coatings include carnauba wax. The content of the glossing agent used in the coating may be 0.0001 to 0.1% by weight, preferably 0.001 to 0.01% by weight, relative to the pharmaceutical composition.
As inorganic substances that are expected to have a stabilizing effect on istradefylline and can be used in coating, the inorganic substances that are expected to have a stabilizing effect on istradefylline as described above can be used as appropriate. Examples of preferred inorganic substances that are expected to have a stabilizing effect on istradefylline and can be used in coating include titanium dioxide and talc. The content of the inorganic substance that is expected to have a stabilizing effect on istradefylline used in coating may be 0.01 to 10% by weight, preferably 0.05 to 1% by weight, relative to the pharmaceutical composition.

The pharmaceutical compositions provided by the present invention can be manufactured by methods known in the pharmaceutical field. For example, in the case of tablets, the manufacturing method may include a mixing step of mixing istradefylline with a coloring agent, a tableting pressure-relieving substance, and optionally other additives, a granulation step, a tableting step, and/or a coating step.
The mixing process can be carried out using methods known in the pharmaceutical field, such as using a V-type mixer, W-type mixer, container mixer, tumbler mixer, or agitator mixer.
The granulation process can be carried out using granulation methods known in the pharmaceutical field. Examples of granulation methods include dry granulation, wet granulation, and fluidized bed granulation. After preparing granules containing istradefylline, additives (for example, excipients such as D-mannitol, disintegrants such as crospovidone, fluidizers such as magnesium aluminometasilicate, and/or lubricants such as magnesium stearate) may be added to the granules and mixed before tableting.
In one embodiment, the mixture obtained in the mixing step or the granules obtained in the granulation step can be appropriately ground and/or sieved to obtain a mixture or granules having a desired particle size. Grinding can be performed using a grinder known in the pharmaceutical field, such as a ball mill, jet mill, or hammer mill. Sieving can be performed using a 16-mesh sieve (mesh opening 1000 μm) to a 32-mesh sieve (mesh opening 500 μm), etc.
The tableting process can be carried out using tableting methods known in the pharmaceutical field. Examples of tableting methods include direct tableting, dry tableting, wet tableting, and external lubrication tableting. For example, the mixture or granules obtained in the above process can be tableted using tablet presses known in the pharmaceutical field, such as single-pull tablet presses or rotary tablet presses. When using single-pull tablet presses, rotary tablet presses, etc., a tableting pressure of 1 kN to 30 kN, preferably 1 to 10 kN, and more preferably 1 to 5 kN can be used.
In one embodiment, when a mixture (e.g., granules) containing istradefylline and a coloring agent (e.g., iron oxide, yellow iron trioxide) is compressed to produce tablets (e.g., tablets with a diameter of approximately 7 mm), the upper limit of the compression pressure is preferably 30 kN, and the lower limit of the compression pressure is preferably a compression pressure that can achieve a tablet hardness of 20 N. For example, a mixture (e.g., granules) containing istradefylline and a coloring agent (e.g., iron oxide, yellow iron trioxide) may be compressed at compression pressures of 1 kN to 30 kN, 1 kN to 25 kN, 1 kN to 20 kN, 1 kN to 10 kN, 1 kN to 5 kN, 5 kN to 30 kN, 5 kN to 25 kN, 5 kN to 20 kN, 10 kN to 30 kN, 10 kN to 25 kN, or 10 kN to 20 kN.
In one embodiment, when a mixture (e.g., granules) containing istradefylline and a lubricant (e.g., magnesium stearate, calcium stearate, sodium stearyl fumarate) is compressed to produce tablets (e.g., tablets with a diameter of approximately 7 mm), the upper limit of the compression pressure is preferably 10 kN, and the lower limit of the compression pressure is preferably a compression pressure that can achieve a tablet hardness of 20 N. For example, a mixture (e.g., granules) containing istradefylline and a lubricant (e.g., magnesium stearate, calcium stearate, sodium stearyl fumarate) may be compressed at a pressure of 1 kN to 10 kN, 1 kN to 5 kN, or 5 kN to 10 kN.
In one embodiment, when a mixture (e.g., granules) containing istradefylline and a lubricant (e.g., magnesium stearate, calcium stearate, sodium stearyl fumarate) but without a coloring agent (e.g., iron oxide, yellow ferric oxide) is compressed to produce tablets (e.g., tablets with a diameter of approximately 7 mm), the upper limit of the compression pressure is preferably 10 kN, and the lower limit of the compression pressure is preferably a compression pressure that can achieve a tablet hardness of 20 N. For example, a mixture (e.g., granules) containing istradefylline and a lubricant (e.g., magnesium stearate, calcium stearate, sodium stearyl fumarate) but without a coloring agent (e.g., iron oxide, yellow ferric oxide) may be compressed at a pressure of 1 kN to 10 kN, 1 kN to 5 kN, or 5 kN to 10 kN.
In one embodiment, when a mixture (e.g., granules) containing istradefylline, a lubricant, and a coloring agent (e.g., iron oxide, yellow iron trioxide) is compressed to produce tablets (e.g., tablets with a diameter of approximately 7 mm), the upper limit of the compression pressure is preferably 30 kN, and the lower limit of the compression pressure is preferably a compression pressure that can achieve a tablet hardness of 20 N. For example, a mixture (e.g., granules) containing istradefylline and a coloring agent (e.g., iron oxide, yellow iron trioxide) may be compressed at compression pressures of 1 kN to 30 kN, 1 kN to 25 kN, 1 kN to 20 kN, 1 kN to 10 kN, 1 kN to 5 kN, 5 kN to 30 kN, 5 kN to 25 kN, 5 kN to 20 kN, 10 kN to 30 kN, 10 kN to 25 kN, or 10 kN to 20 kN.
The coating process can be carried out by methods known in the pharmaceutical field. For example, it can be carried out by spray coating the outside of the istradefylline active pharmaceutical ingredient, granules, or uncoated tablets with a coating solution containing a coating base and appropriate amounts of plasticizers, colorants, and glossing agents.

The pharmaceutical composition provided by the present invention may have improved istradefylline elution by preparing granules containing istradefylline using a wet granulation method. Therefore, the method for producing the pharmaceutical composition provided by the present invention may include a step of preparing granules containing istradefylline using a wet granulation method.
Furthermore, the pharmaceutical composition provided by the present invention may eliminate the need for i) istradefylline active pharmaceutical ingredient, ii) granules containing istradefylline, and iii) coating of the istradefylline-containing tablets by including a mixture of istradefylline and a coloring agent (e.g., yellow iron oxide) in the uncoated tablet. Therefore, the method for producing the pharmaceutical composition provided by the present invention may or may not include a step of coating the istradefylline active pharmaceutical ingredient, granules containing istradefylline, or uncoated tablets containing istradefylline.
Furthermore, the pharmaceutical composition provided by the present invention may be made by including a mixture of istradefylline and a coloring agent (e.g., yellow iron oxide) in the uncoated tablet, thereby coating i) istradefylline active pharmaceutical ingredient, ii) granules containing istradefylline, and iii) uncoated tablets containing istradefylline, and the coating layer may not contain any inorganic substances (e.g., talc, titanium dioxide, and combinations thereof) or coloring agents (e.g., yellow iron oxide) that are expected to have a stabilizing effect on istradefylline. Therefore, the method for producing the pharmaceutical composition provided by the present invention may or may not include a step of coating i) istradefylline active pharmaceutical ingredient, ii) granules containing istradefylline, or iii) uncoated tablets containing istradefylline with a coating layer containing inorganic substances (e.g., talc, titanium dioxide, and combinations thereof) and/or coloring agents (e.g., yellow iron oxide) that are expected to have a stabilizing effect on istradefylline.

Therefore, an example of a pharmaceutical composition provided by the present invention, manufactured by a method including the above steps, is:
i) Uncoated tablets containing istradefylline, in which neither the istradefylline active pharmaceutical ingredient nor the istradefylline-containing granules are coated;
ii) Tablets containing istradefylline, wherein the istradefylline active pharmaceutical ingredient, granules containing istradefylline, and/or the istradefylline-containing tablet within the tablet are coated with a coating layer containing an inorganic substance (e.g., talc, titanium dioxide, and combinations thereof) that is expected to have a stabilizing effect on istradefylline;
iii) Tablets containing istradefylline, wherein the istradefylline active pharmaceutical ingredient, granules containing istradefylline, and/or the istradefylline-containing tablet are coated with a coating layer containing a coloring agent (e.g., yellow ferric oxide);
iv) Tablets containing istradefylline, wherein the istradefylline active pharmaceutical ingredient, granules containing istradefylline, and/or the istradefylline-containing tablet within the tablet are coated with a coating layer that does not contain inorganic substances (e.g., talc, titanium dioxide, and combinations thereof) that are expected to have a stabilizing effect on istradefylline;
v) Tablets containing istradefylline, wherein the istradefylline active pharmaceutical ingredient, istradefylline-containing granules and/or istradefylline-containing tablets in the tablet are coated with a coating layer that does not contain a coloring agent (e.g., yellow ferric oxide);
vi) Tablets containing a mixture of istradefylline and a coloring agent (e.g., yellow iron oxide) in the uncoated tablet, in which the istradefylline active ingredient and istradefylline-containing granules in the uncoated tablet are not coated; and vii) Tablets containing a mixture of istradefylline and a coloring agent (e.g., yellow iron oxide) in the uncoated tablet, in which the istradefylline active ingredient, istradefylline-containing granules and istradefylline-containing uncoated tablet are coated, but the coating layer does not contain any inorganic substances (e.g., talc, titanium dioxide and combinations thereof) or coloring agents (e.g., yellow iron oxide) that are expected to have a stabilizing effect on istradefylline.

When the pharmaceutical composition provided by the present invention contains a mixture of istradefylline and a coloring agent (e.g., yellow iron oxide) in the uncoated tablet, the photodegradation of istradefylline can be suppressed. Therefore, in order to suppress the photodegradation of istradefylline, it is not necessary to include in the pharmaceutical composition any inorganic substances (e.g., talc, titanium dioxide, and combinations thereof) or coloring agents (e.g., yellow iron oxide) that are expected to have a stabilizing effect on istradefylline. In this case, by not using inorganic substances and coloring agents that are expected to have a stabilizing effect on istradefylline, the weight of the formulation can be reduced and the size can be made smaller, which is an advantage.
When the pharmaceutical composition provided by the present invention contains a mixture of istradefylline and a coloring agent (e.g., yellow iron(III) oxide) in the uncoated tablet, the photodegradation of istradefylline can be suppressed, and therefore, coating is not required to suppress the photodegradation of istradefylline. In this case, the advantage is that the weight of the formulation can be reduced and the size can be miniaturized by not applying a coating.
If the pharmaceutical composition provided by the present invention contains a mixture of istradefylline and a coloring agent (e.g., yellow iron oxide) in the uncoated tablet, with the coloring agent (e.g., yellow iron oxide) at a concentration of 1 to 50% by weight, preferably 5 to 30% by weight, and more preferably 10 to 30% by weight relative to the istradefylline, then the photodegradation of istradefylline can be suppressed. Therefore, to suppress the photodegradation of istradefylline, it is not necessary to include inorganic substances (e.g., talc, titanium dioxide, and combinations thereof) and coloring agents (e.g., yellow iron oxide) in the pharmaceutical composition, which are expected to have a stabilizing effect on istradefylline. In this case, by not using inorganic substances and coloring agents that are expected to have a stabilizing effect on istradefylline, the weight of the formulation can be reduced, and it can be made smaller, which is an advantage.
If the pharmaceutical composition provided by the present invention contains a mixture of istradefylline and a coloring agent (e.g., yellow iron oxide) in a tablet, with the coloring agent (e.g., yellow iron oxide) at a concentration of 1 to 50% by weight, preferably 5 to 30% by weight, and more preferably 10 to 30% by weight relative to the istradefylline, then the photodegradation of istradefylline can be suppressed, and therefore, coating is not required to suppress the photodegradation of istradefylline. In this case, the absence of coating has the advantage of reducing the weight of the formulation and enabling miniaturization.
When the pharmaceutical composition provided by the present invention is a tablet containing a mixture of istradefylline and a coloring agent (e.g., yellow ferric oxide) in an uncoated tablet (e.g., an uncoated tablet, an orally disintegrating tablet that is an uncoated tablet, a film-coated orally disintegrating tablet, or a film-coated tablet), the photodegradation of istradefylline in the crushed tablet is suppressed in the same way as in the uncrushed tablet. In this case, there is the advantage that the tablet can be crushed and administered to patients with dysphagia.
When the pharmaceutical composition provided by the present invention is a tablet containing a mixture of istradefylline and a coloring agent (e.g., yellow ferric oxide) in an uncoated tablet, with the coloring agent (e.g., yellow ferric oxide) at a concentration of 1 to 50% by weight, preferably 5 to 30% by weight, and more preferably 10 to 30% by weight relative to the istradefylline (e.g., an uncoated tablet, an orally disintegrating tablet that is an uncoated tablet, a film-coated orally disintegrating tablet, or a film-coated tablet), the photodegradation of istradefylline in the crushed tablet is suppressed in the same way as in the uncrushed tablet. In this case, there is the advantage that the tablet can be crushed and administered to patients with dysphagia.

In one embodiment, the pharmaceutical composition provided by the present invention (e.g., uncoated tablets, uncoated orally disintegrating tablets, film-coated orally disintegrating tablets, film-coated tablets) does not contain crystalline cellulose.
In one embodiment, istradefylline contained in the pharmaceutical composition provided by the present invention (e.g., uncoated tablets, orally disintegrating tablets that are uncoated, film-coated orally disintegrating tablets, film-coated tablets) has an average particle size greater than 20 μm (e.g., greater than 20 μm and less than or equal to 70 μm, greater than 20 μm and less than 50 μm, 25 μm and greater than or equal to 40 μm).
In one embodiment, the istradefylline contained in the pharmaceutical composition provided by the present invention (e.g., uncoated tablets, orally disintegrating tablets that are uncoated, film-coated orally disintegrating tablets, film-coated tablets) has an average particle size greater than 20 μm (e.g., greater than 20 μm and less than or equal to 70 μm, greater than 20 μm and less than 50 μm, 25 μm and less than or equal to 40 μm), and the pharmaceutical composition does not contain crystalline cellulose.
In one embodiment, the orally disintegrating tablet provided by the present invention has a hardness of 20 N or more, more preferably 30 N or more (for example, 50 N or more, 65 N or more, 70 N or more, 20 N or more and 60 N or less, 20 N or more and 100 N or less, 30 N or more and 100 N or less, 70 N or more and 100 N or less, 70 N or more and 150 N or less), and disintegrates in the oral cavity within 60 seconds (for example, within 10 seconds to 60 seconds).
In one embodiment, the orally disintegrating tablet provided by the present invention has a hardness of 20 N or more, more preferably 30 N or more (for example, 50 N or more, 65 N or more, 70 N or more, 20 N or more and 60 N or less, 20 N or more and 100 N or less, 30 N or more and 100 N or less, 70 N or more and 100 N or less, 70 N or more and 150 N or less), disintegrates in the oral cavity within 60 seconds (for example, within 10 seconds to 60 seconds), and inhibits the photodegradation of istradefylline.
In one embodiment, the orally disintegrating tablets provided by the present invention have no bitterness or astringency and exhibit a pleasant taste.
In one embodiment, the pharmaceutical composition provided by the present invention (for example, a plain tablet, an orally disintegrating tablet that is a plain tablet, a film-coated orally disintegrating tablet, or a film-coated tablet) contains D-mannitol, lactose monohydrate, or anhydrous calcium hydrogen phosphate.
In one embodiment, the pharmaceutical composition provided by the present invention (e.g., uncoated tablets, orally disintegrating tablets that are uncoated, film-coated orally disintegrating tablets, film-coated tablets) comprises magnesium stearate, calcium stearate, or sodium stearyl fumarate.
In one embodiment, the pharmaceutical composition provided by the present invention (e.g., uncoated tablets, orally disintegrating tablets that are uncoated, film-coated orally disintegrating tablets, film-coated tablets) comprises D-mannitol and a lubricant, wherein the lubricant is magnesium stearate, calcium stearate, or sodium stearyl fumarate.
In one embodiment, the pharmaceutical composition provided by the present invention (e.g., uncoated tablets, orally disintegrating tablets that are uncoated, film-coated orally disintegrating tablets, film-coated tablets) comprises D-mannitol and a lubricant, wherein the lubricant is magnesium stearate, calcium stearate, or sodium stearyl fumarate, and the content of the lubricant is 5% by weight or less (e.g., 2% by weight or less, 0.1 to 1% by weight).

The pharmaceutical composition provided by the present invention as described above suppresses photodegradation of istradefylline and stabilizes istradefylline. Therefore, the present invention provides a method for suppressing photodegradation of istradefylline or a method for stabilizing istradefylline (a method for stabilizing istradefylline against light) by manufacturing the above-described pharmaceutical composition (e.g., a solid dosage form). Accordingly, in one embodiment, the present invention provides a method for suppressing photodegradation of istradefylline or a method for stabilizing istradefylline (a method for stabilizing istradefylline against light) that includes steps for manufacturing the above-described pharmaceutical composition (e.g., a solid dosage form) (e.g., a mixing step, a granulation step, a coating step, and/or a tableting step). The photodegradation inhibitory effect or light-stabilizing effect of istradefylline can be evaluated by, with reference to Japanese Patent No. 4673745, in accordance with the ICH Guidelines for Photostability Testing of New Active Pharmaceutical Ingredients and New Formulations (November 6, 1996), exposing the pharmaceutical composition provided by the present invention to a total illuminance of 1,200,000 Lux·hr or more using a xenon lamp as the light source, then sampling, and determining the total amount of istradefylline degradation products by HPLC analysis.
In one embodiment, the pharmaceutical composition provided by the present invention exhibits a photodegradation of istradefylline upon exposure to a total illuminance of 1,200,000 Lux·hr or more, which is 1% or less of the amount of istradefylline before exposure (for example, 0.4% or less or 0.1% or less).
In one embodiment, the pharmaceutical composition provided by the present invention has a photodegradable product (e.g., a dimer) of istradefylline produced by exposure to a total illuminance of 1,200,000 Lux·hr or more that is 0.5% or less (e.g., 0.4% or less or 0.1% or less) of the amount of istradefylline before exposure.
Examples of photodegradable products of istradefylline include dimers. Therefore, in one embodiment, the method for suppressing the photodegradation of istradefylline or stabilizing istradefylline (a method for stabilizing with respect to light) provided by the present invention may be a method for suppressing the formation of istradefylline dimers.

The present invention provides a method for inhibiting the photodegradation of istradefylline or a method for stabilizing istradefylline (a method for stabilizing istradefylline against light), which may include the steps of: preparing a mixture of istradefylline and a coloring agent (e.g., granules); preparing a mixture of istradefylline and a tableting pressure-relieving substance (e.g., granules); or preparing a mixture of istradefylline, a coloring agent, and a tableting pressure-relieving substance (e.g., granules).
The present invention provides a method for inhibiting the photodegradation of istradefylline or a method for stabilizing istradefylline (a method for stabilizing it against light),
A step of mixing at least one coloring agent and a tableting pressure-relieving substance with istradefylline, and granulating the resulting mixture;
A step of coating at least one of the istradefylline active pharmaceutical ingredient, granules, and uncoated tablets (for example, a step of coating with a coating layer containing at least one inorganic substance (e.g., talc, titanium dioxide, and a combination thereof) and a coloring agent (e.g., yellow iron oxide) that is expected to have a stabilizing effect on istradefylline, or a step of coating with a coating layer that does not contain at least one of the inorganic substance (e.g., talc, titanium dioxide, and a combination thereof) and a coloring agent (e.g., yellow iron oxide) that is expected to have a stabilizing effect on istradefylline); and a tableting step (the tableting pressure may be, for example, 30 kN or less, 20 kN or less, 10 kN or less, 1 kN or more and 30 kN or less, or 1 kN or more and 10 kN or less).
It may include at least one of the following steps.

Examples of other embodiments provided by the present invention include (1) to (1-17) and (A1) to (A1-27) below.
(1) A pharmaceutical composition (e.g., a solid dosage form) comprising a mixture of istradefylline and a coloring agent (e.g., yellow iron(III) oxide);
(2) A pharmaceutical composition (e.g., a solid dosage form) comprising a mixture of istradefylline and a tablet pressure-relieving substance;
(3) A pharmaceutical composition (e.g., a solid dosage form) comprising a mixture of istradefylline, a coloring agent (e.g., yellow ferric oxide), and a tablet pressure-relieving substance;
(4) The pharmaceutical composition according to (2) or (3) (e.g., a solid dosage form), wherein the tablet pressure relief agent is a lubricant selected from the group consisting of magnesium stearate, calcium stearate, and sodium stearyl fumarate;
(5) A pharmaceutical composition according to any one of (1) to (4) (for example, a solid dosage form), wherein the pharmaceutical composition is a tablet and the mixture is a granule;
(6) A pharmaceutical composition according to any one of (1) to (5) (e.g., a solid dosage form), wherein the pharmaceutical composition is a tablet, the mixture is a granule, and none of the istradefylline active pharmaceutical ingredient, the granule, or the uncoated tablet are coated with a coating layer containing an inorganic substance (e.g., talc, titanium dioxide, or a combination thereof) and/or a coloring agent (e.g., yellow iron oxide) that is expected to have a stabilizing effect on istradefylline;
(7) A pharmaceutical composition according to any one of (1) to (6) (for example, a solid dosage form), wherein the pharmaceutical composition is a tablet;
(8) A pharmaceutical composition according to any one of (1) to (7) (for example, a solid dosage form), wherein the pharmaceutical composition is an orally disintegrating tablet;
(9) A pharmaceutical composition according to any one of (1) to (8) (e.g., a solid dosage form);
(10) A pharmaceutical composition according to any one of (1) to (9) (e.g., a solid dosage form) in which the photodegradation of istradefylline is suppressed;
(11) A pharmaceutical composition (e.g., solid dosage form) according to any one of (1) to (10), wherein the photodegradable product (e.g., dimer) of istradefylline produced by exposure to a total illuminance of 1,200,000 Lux·hr or more is 0.5% or less (e.g., 0.4% or less or 0.1% or less) of the amount of istradefylline before exposure;
(12) A pharmaceutical composition according to any one of (1) to (11) (e.g., a solid dosage form), wherein the pharmaceutical composition is a tablet and has a hardness of 20 N or more (e.g., 60 N or more);
(13) A pharmaceutical composition (e.g., a solid dosage form) according to any of (1) to (12), wherein the pharmaceutical composition is an orally disintegrating tablet, and according to the disintegration test of the 17th edition of the Japanese Pharmacopoeia, the orally disintegrating tablet disintegrates within 60 seconds;
(14) A pharmaceutical composition (e.g., a solid dosage form) according to any one of (1) to (13), wherein the istradefylline has an average particle size of more than 20 μm and less than or equal to 200 μm (for example, more than 20 μm and less than or equal to 70 μm, or 50 μm and less than or equal to 100 μm);
(15) A pharmaceutical composition according to any one of (1) to (14) that does not contain crystalline cellulose (for example, a solid dosage form);
(16) A pharmaceutical composition according to any one of (1) to (15) (for example, a solid dosage form), comprising D-mannitol, lactose monohydrate, or anhydrous calcium hydrogen phosphate as an excipient;
(1-1) A method for producing a pharmaceutical composition (e.g., a solid dosage form) containing istradefylline, or a method for inhibiting the photodegradation of istradefylline in a pharmaceutical composition, comprising the step of preparing a mixture of istradefylline and a coloring agent (e.g., yellow iron oxide);
(1-2) A method for producing a pharmaceutical composition (e.g., a solid dosage form) containing istradefylline, comprising the step of preparing a mixture of istradefylline and a tablet pressure-relieving substance, or a method for inhibiting the photodegradation of istradefylline in a pharmaceutical composition;
(1-3) A method for producing a pharmaceutical composition (e.g., a solid dosage form) containing istradefylline, or a method for inhibiting the photodegradation of istradefylline in a pharmaceutical composition, comprising the step of preparing a mixture of istradefylline, a coloring agent (e.g., yellow iron oxide), and a tablet pressure-relieving substance;
(1-4) The method according to (1-2) or (1-3), wherein the tableting pressure-relieving agent is a lubricant selected from the group consisting of magnesium stearate, calcium stearate, and sodium stearyl fumarate;
(1-5) The method according to any one of (1-1) to (1-4), wherein the pharmaceutical composition is a tablet and the mixture is a granule;
(1-6) The method according to any one of (1-1) to (1-7), wherein the pharmaceutical composition is a tablet, the mixture is a granule, and none of the istradefylline active pharmaceutical ingredient, granule, or uncoated tablet are coated with a coating layer containing an inorganic substance (e.g., talc, titanium dioxide, and combinations thereof) and/or a coloring agent (e.g., yellow iron(III) oxide) that is expected to have a stabilizing effect on istradefylline;
(1-7) The method according to any one of (1-1) to (1-6), wherein the pharmaceutical composition is a plain tablet;
(1-8) The method according to any one of (1-1) to (1-7), wherein the pharmaceutical composition is an orally disintegrating tablet;
(1-9) The method according to any one of (1-1) to (1-8), wherein the pharmaceutical composition contains crospovidone;
(1-10) The method according to any one of (1-1) to (1-9), comprising the step of granulating a mixture, wherein the granulation is carried out by wet granulation;
(1-11) The method according to any one of (1-1) to (1-10), wherein the amount of photodegraded istradefylline in the pharmaceutical composition (e.g., dimers) produced as a result of exposing the pharmaceutical composition to a total illuminance of 1,200,000 Lux·hr or more is 0.5% or less (e.g., 0.4% or less or 0.1% or less) of the amount of istradefylline before exposure;
(1-12) The pharmaceutical composition is a tablet with a hardness of 20 N or more (for example, 60 N or more), according to any of the methods (1-1) to (1-11); and (1-13) The pharmaceutical composition is an orally disintegrating tablet, and according to the disintegration test of the 17th edition of the Japanese Pharmacopoeia, the orally disintegrating tablet disintegrates within 60 seconds, according to the method according to any of the methods (1-1) to (1-12);
(1-14) The method according to any one of (1-1) to (1-13), wherein the istradefylline is istradefylline having an average particle size of more than 20 μm and less than or equal to 200 μm (for example, more than 20 μm and less than or equal to 70 μm);
(1-15) The method according to any one of (1-1) to (1-14), wherein the pharmaceutical composition does not contain crystalline cellulose;
(1-16) The method according to any one of (1-1) to (1-15), wherein the pharmaceutical composition contains D-mannitol, lactose monohydrate, or anhydrous calcium hydrogen phosphate as an excipient;
(1-17) The method according to any one of (1-1) to (1-16), wherein the pharmaceutical composition is a tablet, and the tablet is compressed with a compression pressure of 30 kN or less or 10 kN or less;
(A1)
A pharmaceutical composition (e.g., a solid dosage form) comprising at least one substance selected from the group consisting of D-mannitol and anhydrous calcium hydrogen phosphate, and istradefylline;
(A2)
A pharmaceutical composition according to (A1) (e.g., a solid dosage form), comprising D-mannitol and istradefylline;
(A3)
A pharmaceutical composition according to (A1) (e.g., a solid dosage form), comprising anhydrous calcium hydrogen phosphate and istradefylline;
(A4)
A pharmaceutical composition (e.g., a solid dosage form) according to any one of (A1) to (A3), further comprising a lubricant;
(A5)
A pharmaceutical composition (e.g., a solid dosage form) comprising istradefylline and a lubricant;
(A6)
A pharmaceutical composition (e.g., a solid dosage form) according to (A4) or (A5) wherein the content of the lubricant is 5% by weight or less;
(A7)
A pharmaceutical composition (e.g., solid dosage form) according to any one of (A4) to (A6), wherein the lubricant is selected from at least one of the group consisting of magnesium stearate, calcium stearate, and sodium stearyl fumarate;
(A8)
A pharmaceutical composition (e.g., a solid dosage form) containing a coloring agent, according to any one of (A1) to (A7);
(A9)
A pharmaceutical composition (e.g., a solid dosage form) according to (A8), wherein the coloring agent is selected from at least one of the group consisting of iron oxide, yellow iron(III) oxide, yellow iron oxide, food yellow No. 4 aluminum lake, food yellow No. 5 aluminum lake, red iron oxide, iron(III) oxide, food red No. 2, food red No. 3, food red No. 102, black iron oxide, carmine-P, riboflavin, yellow No. 5, carbon black, and medicinal charcoal;
(A10)
A pharmaceutical composition (e.g., a solid dosage form) according to (A8) or (A9), wherein the coloring agent is iron oxide;
(A11)
A pharmaceutical composition (e.g., a solid dosage form) according to (A8) or (A9), wherein the coloring agent is yellow iron(III) oxide;
(A12)
A pharmaceutical composition (e.g., a solid dosage form) comprising D-mannitol, a lubricant, a colorant, and istradefylline;
(A13)
A pharmaceutical composition (e.g., a solid dosage form) according to (A12), wherein the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, and sodium stearyl fumarate;
(A14)
A pharmaceutical composition (e.g., a solid dosage form) according to (A12) or (A13), wherein the coloring agent is selected from at least one of the group consisting of iron oxide, yellow iron(III) oxide, yellow iron oxide, food red (III), food red (III), food red (III), food red (III), food red (III), food red (III), black iron oxide, carmine-P, riboflavin, yellow (III), carbon black, and medicinal charcoal;
(A15)
A pharmaceutical composition (e.g., a solid dosage form) comprising D-mannitol, calcium stearate, yellow ferric oxide, and istradefylline;
(A16)
A mixture comprising at least one substance selected from the group consisting of D-mannitol and anhydrous calcium hydrogen phosphate and istradefylline; or,
A mixture containing a lubricant and istradefylline,
A pharmaceutical composition (e.g., a solid dosage form) according to any one of (A1) to (A15), including the above;
(A17)
A pharmaceutical composition (e.g., a solid dosage form) according to (A16), wherein the mixture is a granule;
(A18)
A pharmaceutical composition according to (A16) or (A17) (e.g., a solid dosage form) comprising a coloring agent in the mixture;
(A19)
A pharmaceutical composition (e.g., a solid dosage form) according to any one of (A16) to (A18), wherein the mixture is a granule, and the granule is coated with a coating layer containing titanium dioxide and/or talc or a coating layer not containing titanium dioxide and/or talc;
(A20)
A pharmaceutical composition (e.g., a solid dosage form) according to any one of (A1) to (A19), wherein the pharmaceutical composition (e.g., a solid dosage form) is a fine granule, a granule, a tablet, a capsule, or a dry syrup;
(A21)
A pharmaceutical composition (e.g., a solid dosage form) according to any one of (A1) to (A20), wherein the pharmaceutical composition (e.g., a solid dosage form) is an orally disintegrating tablet;
(A22)
A pharmaceutical composition (e.g., a solid dosage form) that does not contain crystalline cellulose, as described in any of (A1) to (A20);
(A23)
A pharmaceutical composition (e.g., a solid dosage form) according to any one of (A1) to (A22), which is a tablet containing at least one substance selected from the group consisting of D-mannitol and anhydrous calcium hydrogen phosphate and istradefylline in the uncoated tablet, or a tablet containing a lubricant and istradefylline in the uncoated tablet;
(A24)
A pharmaceutical composition (e.g., a solid dosage form) according to (A23), wherein the uncoated tablet is coated with a coating layer containing titanium dioxide and/or talc or a coating layer not containing titanium dioxide and/or talc;
(A25)
A pharmaceutical composition (e.g., a solid dosage form) according to any one of (A1) to (A24), wherein the photodegradation of istradefylline in the pharmaceutical composition (e.g., a solid dosage form) upon exposure to a total illuminance of 1,200,000 Lux·hr or more is 1% or less;
(A26)
A pharmaceutical composition (e.g., a solid dosage form) according to any one of (A1) to (A25), wherein the pharmaceutical composition (e.g., a solid dosage form) is a tablet and has a hardness of 20 N or more;
(A27)
A pharmaceutical composition (e.g., a solid dosage form) that is an orally disintegrating tablet, and which disintegrates within 60 seconds according to the disintegration test of the 17th edition of the Japanese Pharmacopoeia, as described in any of (A1) to (A26);
(A28)
A pharmaceutical composition (e.g., a solid dosage form) according to any one of (A1) to (A27), wherein the istradefylline is istradefylline having an average particle size of more than 20 μm and less than or equal to 200 μm;
(A29)
A pharmaceutical composition (e.g., a solid dosage form) according to any one of (A1) to (A28), wherein the pharmaceutical composition (e.g., a solid dosage form) further comprises a disintegrant;
(A30)
A pharmaceutical composition (e.g., a solid dosage form) according to any one of (A1) to (A29), wherein the disintegrant is crospovidone;
(A1-1)
A method for producing a pharmaceutical composition containing istradefylline (e.g., a solid dosage form) or a method for inhibiting the photodegradation of istradefylline in a pharmaceutical composition, comprising the step of preparing a mixture containing at least one substance selected from the group consisting of D-mannitol and anhydrous calcium hydrogen phosphate, and istradefylline;
(A1-2)
A method for producing a pharmaceutical composition containing istradefylline (e.g., a solid dosage form) as described in (A1-1), or a method for inhibiting the photodegradation of istradefylline in a pharmaceutical composition, comprising the step of preparing a mixture containing D-mannitol and istradefylline;
(A1-3)
A method for producing a pharmaceutical composition containing istradefylline (e.g., a solid dosage form) as described in (A1-1), or a method for inhibiting the photodegradation of istradefylline in a pharmaceutical composition, comprising the step of preparing a mixture containing anhydrous calcium hydrogen phosphate and istradefylline;
(A1-4)
A method for producing a pharmaceutical composition (e.g., a solid dosage form) according to any one of (A1-1) to (A1-3), wherein the mixture further comprises a lubricant, or a method for inhibiting the photodegradation of istradefylline in a pharmaceutical composition;
(A1-5)
A method for producing a pharmaceutical composition containing istradefylline (e.g., a solid dosage form), comprising the step of preparing a mixture containing istradefylline and a lubricant, or a method for inhibiting the photodegradation of istradefylline in a pharmaceutical composition;
(A1-6)
A method for producing a pharmaceutical composition (e.g., a solid dosage form) containing istradefylline as described in (A1-4) or (A1-5), wherein the content of the lubricant is 5% by weight or less, or a method for inhibiting the photodegradation of istradefylline in a pharmaceutical composition;
(A1-7)
A method for producing a pharmaceutical composition (e.g., a solid dosage form) containing istradefylline according to any one of (A1-4) to (A1-6), wherein the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, and sodium stearyl fumarate, wherein the lubricant is selected from at least one of these groups; or a method for inhibiting the photodegradation of istradefylline in a pharmaceutical composition.
(A1-8)
A method for producing a pharmaceutical composition containing istradefylline (e.g., a solid dosage form) according to any one of (A1-4) to (A1-7), further comprising the step of compressing a mixture containing istradefylline and a lubricant into tablets, wherein the tableting pressure is 10 kN or less; or a method for inhibiting the photodegradation of istradefylline in a pharmaceutical composition;
(A1-9)
A method for producing a pharmaceutical composition (e.g., a solid dosage form) containing istradefylline according to any one of (A1-1) to (A1-8), or a method for inhibiting the photodegradation of istradefylline in a pharmaceutical composition (e.g., a solid dosage form) containing a coloring agent (e.g., contained in a mixture);
(A1-10)
A method for producing a pharmaceutical composition (e.g., a solid dosage form) containing istradefylline as described in (A1-9), wherein the coloring agent is selected from at least one of the group consisting of iron oxide, yellow iron oxide, yellow iron oxide, food yellow No. 4 aluminum lake, food yellow No. 5 aluminum lake, red iron oxide, iron oxide, food red No. 2, food red No. 3, food red No. 102, black iron oxide, carmine-P, riboflavin, yellow No. 5, carbon black, and medicinal charcoal, or a method for inhibiting the photodegradation of istradefylline in a pharmaceutical composition;
(A1-11)
A method for producing a pharmaceutical composition (e.g., a solid dosage form) containing istradefylline as described in (A1-9) or (A1-10), wherein the coloring agent is iron oxide, or a method for inhibiting the photodegradation of istradefylline in a pharmaceutical composition;
(A1-12)
A method for producing a pharmaceutical composition (e.g., a solid dosage form) containing istradefylline as described in (A1-9) or (A1-10), wherein the coloring agent is yellow iron(III) oxide; or a method for inhibiting the photodegradation of istradefylline in a pharmaceutical composition;
(A1-13)
A method for producing a pharmaceutical composition containing istradefylline (e.g., a solid dosage form) according to any one of (A1-9) to (A1-12), further comprising the step of compressing a mixture containing istradefylline and a coloring agent into tablets, wherein the compression pressure is 30 kN or less; or a method for inhibiting the photodegradation of istradefylline in a pharmaceutical composition;
(A1-14)
A method for producing a pharmaceutical composition (e.g., a solid dosage form) containing istradefylline according to any one of (A1-1) to (A1-13), wherein the step of preparing a mixture includes a step of preparing granules, or a method for inhibiting the photodegradation of istradefylline in a pharmaceutical composition;
(A1-15)
A method for producing a pharmaceutical composition (e.g., a solid dosage form) containing istradefylline according to any one of (A1-1) to (A1-14), wherein the steps include preparing a mixture, preparing granules, and coating the obtained granules with a coating layer containing titanium dioxide and/or talc or a coating layer not containing titanium dioxide and/or talc; or a method for inhibiting the photodegradation of istradefylline in a pharmaceutical composition;
(A1-16)
A method for producing a pharmaceutical composition (e.g., a solid dosage form) containing istradefylline as described in either (A1-14) or (A1-15), wherein the granules are prepared by a wet granulation method, or a method for inhibiting the photodegradation of istradefylline in a pharmaceutical composition;
(A1-17)
A method for producing a pharmaceutical composition (e.g., a solid dosage form) containing istradefylline according to any one of (A1-1) to (A1-16), wherein the pharmaceutical composition (e.g., a solid dosage form) is a fine granule, a granule, a tablet, a capsule, or a dry syrup, or a method for inhibiting the photodegradation of istradefylline in a pharmaceutical composition;
(A1-18)
A method for producing a pharmaceutical composition (e.g., a solid dosage form) containing istradefylline according to any one of (A1-1) to (A1-17), wherein the pharmaceutical composition (e.g., a solid dosage form) is a tablet containing at least one substance selected from the group consisting of D-mannitol and anhydrous calcium hydrogen phosphate and istradefylline in the uncoated tablet, or a tablet containing a lubricant and istradefylline in the uncoated tablet, or a method for inhibiting the photodegradation of istradefylline in a pharmaceutical composition;
(A1-19)
A method for producing a pharmaceutical composition (e.g., a solid dosage form) containing istradefylline as described in (A1-18), wherein the uncoated tablet is coated with a coating layer containing titanium dioxide and/or talc or a coating layer not containing titanium dioxide and/or talc, or a method for inhibiting the photodegradation of istradefylline in a pharmaceutical composition;
(A1-20)
A method for producing a pharmaceutical composition (e.g., a solid dosage form) containing istradefylline according to any one of (A1-1) to (A1-19), wherein the photodegradation of istradefylline in the pharmaceutical composition (e.g., a solid dosage form) by exposure to a total illuminance of 1,200,000 Lux·hr or more is 1% or less, or a method for suppressing the photodegradation of istradefylline in a pharmaceutical composition;
(A1-21)
A method for producing a pharmaceutical composition (e.g., a solid dosage form) containing istradefylline according to any one of (A1-1) to (A1-20), wherein the pharmaceutical composition (e.g., a solid dosage form) is a tablet with a hardness of 20 N or more, or a method for inhibiting the photodegradation of istradefylline in a pharmaceutical composition;
(A1-22)
A method for producing a pharmaceutical composition (e.g., a solid dosage form) containing istradefylline as described in any of (A1-1) to (A1-21), wherein the pharmaceutical composition (e.g., a solid dosage form) is an orally disintegrating tablet, and according to the disintegration test of the 17th edition of the Japanese Pharmacopoeia, the orally disintegrating tablet disintegrates within 60 seconds; or a method for inhibiting the photodegradation of istradefylline in a pharmaceutical composition;
(A1-23)
A method for producing a pharmaceutical composition (e.g., a solid dosage form) containing istradefylline as described in any of (A1-1) to (A1-22), wherein the istradefylline has an average particle size of more than 20 μm and less than or equal to 200 μm, or a method for inhibiting the photodegradation of istradefylline in a pharmaceutical composition;
(A1-24)
A method for producing a pharmaceutical composition (e.g., a solid dosage form) containing istradefylline according to any one of (A1-1) to (A1-23), wherein the pharmaceutical composition (e.g., a solid dosage form) further comprises a disintegrant, or a method for inhibiting the photodegradation of istradefylline in a pharmaceutical composition;
(A1-25)
A method for producing a pharmaceutical composition (e.g., a solid dosage form) containing istradefylline as described in (A1-24), wherein the disintegrant is crospovidone, or a method for inhibiting the photodegradation of istradefylline in a pharmaceutical composition;
(A1-26)
A method for producing a pharmaceutical composition (e.g., a solid dosage form) containing istradefylline as described in any of (A1-1) to (A1-25), which does not contain crystalline cellulose, or a method for inhibiting the photodegradation of istradefylline in a pharmaceutical composition;
(A1-27)
A method for producing a pharmaceutical composition (e.g., a solid dosage form) containing istradefylline according to any one of (A1-1) to (A1-26), wherein the pharmaceutical composition (e.g., a solid dosage form) is a tablet with a hardness of 20 N or more, or a method for inhibiting the photodegradation of istradefylline in a pharmaceutical composition.

The present invention will be further described below with reference to examples, but the present invention is not limited to these examples.

The tablets were prepared as follows:
Example 1: Film-coated tablets
Using a mortar and pestle, istradefylline (10 g; average particle size 53.0 μm (measured using Shimadzu Corporation SALD-2200)), D-manthol (26 g, mannitol C, manufactured by Mitsubishi Corporation Life Sciences, Inc.), anhydrous calcium hydrogen phosphate (12.5 g, Fujikarin, manufactured by Fuji Chemical Industries, Inc.), and hydroxypropyl cellulose (2 g, HPC-L, manufactured by Nippon Soda Co., Ltd.) were mixed, and 8 g of purified water was added to the mixture to granulate it. After granulation, it was dried in a dryer at 50°C. After drying, it was passed through a No. 30 sieve to obtain uniform granules. The obtained whole granules were placed in a plastic bag, and for every 100 parts by weight of whole granules, 29.7 parts by weight of D-mannitol (Parteck M200, Merck KGaA), 5.9 parts by weight of crospovitone (Coridon CL-F, BASF Japan Ltd.), and 2.0 parts by weight of magnesium aluminometasilicate (Neusilin, Fuji Chemical Industry Co., Ltd.) were added and mixed. To this, 1.0 part by weight of magnesium stearate (Taihei Chemical Industry Co., Ltd.) was added and mixed to obtain granules for tableting. Using a tablet press (VELA5, Kikusui Seisakusho Co., Ltd.), the obtained granules for tableting were made into tablets to obtain uncoated tablets (tablet mass: 140 mg, tablet shape: round tablet (φ7.0 mm)).
Next, according to the formulation shown in Figure 1, PVA/PEG kraft copolymer (Colicoat IR, manufactured by BASF Japan Ltd.), titanium dioxide (Wako Pure Chemical Industries, Ltd.), and talc (Crown Talc, Matsumura Sangyo Co., Ltd.) were dissolved and dispersed in purified water to prepare a coating solution with a solid content of 8% by weight. Using a High Coater (HCT-MINI, Freund Industrial Co., Ltd.), the uncoated tablets obtained above were coated so that the dry coating amounted to 2.1 parts by weight per 100 parts by weight of the uncoated tablets, thereby obtaining film-coated tablets.
Example 2: Film-coated tablets
Istradefylline (10g; average particle size 53.0 μm (measured using Shimadzu Corporation SALD-2200)), D-manthol (41g, Parteck M200, Merck KGaA), anhydrous calcium hydrogen phosphate (12.5g, Fujikarin, Fuji Chemical Industries Co., Ltd.), hydroxypropyl cellulose (2g, HPC-L, Nippon Soda Co., Ltd.), crospoviton (3g, Coridon CL-F, BASF Japan Ltd.), and magnesium aluminometasilicate (1g, Neusilin, Fuji Chemical Industries Co., Ltd.) were placed in a plastic bag and mixed. Magnesium stearate (0.5g, Taihei Chemical Industry Co., Ltd.) was added and mixed to obtain tablet granules. Tablets were obtained by manufacturing the obtained tablet granules using a tablet press (VELA5, Kikusui Seisakusho Co., Ltd.) to obtain uncoated tablets (tablet mass: 140 mg, tablet shape: round tablet (φ7.0 mm)).
Next, according to the formulation shown in Figure 1, PVA/PEG kraft copolymer (Coricoat IR, manufactured by BASF Japan Ltd.), titanium dioxide (titanium dioxide, Wako Pure Chemical Industries, Ltd.), and talc (Crown Talc, Matsumura Sangyo Co., Ltd.) were dissolved and dispersed in purified water to prepare a coating solution with a solid content of 8% by weight. Using a High Coater (HCT-MINI, Freund Industrial Co., Ltd.), the uncoated tablets obtained above were coated so that the dry coating amounted to 2.1 parts by weight per 100 parts by weight of the uncoated tablets, thereby obtaining film-coated tablets.
Example 3: Film-coated tablets
Using a mortar and pestle, istradefylline (20 g; average particle size 53.0 μm (measured using Shimadzu Corporation SALD-2200)), D-manthol (45 g, mannitol C, manufactured by Mitsubishi Corporation Life Sciences, Inc.), anhydrous calcium hydrogen phosphate (15 g, Fujikarin, manufactured by Fuji Chemical Industries, Inc.), and hydroxypropyl cellulose (2 g, HPC-L, manufactured by Nippon Soda Co., Ltd.) were mixed, and 14 g of purified water was added to the mixture to granulate it. After granulation, it was dried in a dryer at 50°C. After drying, it was passed through a No. 30 sieve to obtain uniform granules. The obtained whole granules were placed in a plastic bag, and for every 100 parts by weight of whole granules, 57.3 parts by weight of D-mannitol (Parteck M200, Merck KGaA), 9.8 parts by weight of crospovitone (Coridon CL-F, BASF Japan Ltd.), and 2.4 parts by weight of magnesium aluminometasilicate (Neusilin, Fuji Chemical Industry Co., Ltd.) were added and mixed. To this, 1.2 parts by weight of magnesium stearate (Taihei Chemical Industry Co., Ltd.) was added and mixed to obtain granules for tableting. Using a tablet press (VELA5, Kikusui Seisakusho Co., Ltd.), the obtained granules for tableting were made into tablets to obtain uncoated tablets (tablet mass: 140 mg, tablet shape: round tablet (φ7.0 mm)).
Next, according to the formulation shown in Figure 1, PVA/PEG kraft copolymer (Colicoat IR, manufactured by BASF Japan Ltd.), polyethylene glycol (PEG6000P, manufactured by Sanyo Chemical Industries, Ltd.), titanium dioxide (Wako Pure Chemical Industries, Ltd.), and talc (Crown Talc, manufactured by Matsumura Sangyo Co., Ltd.) were dissolved and dispersed in purified water to prepare a coating solution with a solid content of 8% by weight. Using a High Coater (HCT-MINI, manufactured by Freund Industrial Co., Ltd.), the uncoated tablets obtained above were coated so that the dry coating amounted to 2.9 parts by weight per 100 parts by weight of the uncoated tablets, thereby obtaining film-coated tablets.

Example 4: Uncoated Tablets
Using a mortar and pestle, istradefylline (20 g; average particle size 53.0 μm (measured using Shimadzu Corporation SALD-2200)), D-manthol (45 g, mannitol C, manufactured by Mitsubishi Corporation Life Sciences, Inc.), anhydrous calcium hydrogen phosphate (15 g, Fujikarin, manufactured by Fuji Chemical Industries, Inc.), and hydroxypropyl cellulose (2 g, HPC-L, manufactured by Nippon Soda Co., Ltd.) were mixed, and 14 g of purified water was added to the mixture to granulate it. After granulation, it was dried in a dryer at 50°C. After drying, it was passed through a No. 30 sieve to obtain uniform granules. The obtained whole granules were placed in a plastic bag, and for every 100 parts by weight of whole granules, 57.3 parts by weight of D-mannitol (Parteck M200, Merck KGaA), 9.8 parts by weight of crospovitone (Coridon CL-F, BASF Japan Ltd.), and 2.4 parts by weight of magnesium aluminometasilicate (Neusilin, Fuji Chemical Industry Co., Ltd.) were added and mixed. To this, 1.2 parts by weight of magnesium stearate (Taihei Chemical Industry Co., Ltd.) was added and mixed to obtain granules for tableting. Using a tablet press (VELA5, Kikusui Seisakusho Co., Ltd.), the obtained granules for tableting were made into tablets to obtain uncoated tablets (tablet mass: 140 mg, tablet shape: round tablet (φ7.0 mm)).


Example 5: Film-coated tablets
Using a mortar and pestle, istradefylline (20 g; average particle size 53.0 μm (measured using Shimadzu Corporation SALD-2200)), D-manthol (45 g, mannitol C, manufactured by Mitsubishi Corporation Life Sciences, Inc.), anhydrous calcium hydrogen phosphate (15 g, Fujikarin, manufactured by Fuji Chemical Industries, Inc.), and hydroxypropyl cellulose (2 g, HPC-L, manufactured by Nippon Soda Co., Ltd.) were mixed, and 14 g of purified water was added to the mixture to granulate it. After granulation, it was dried in a dryer at 50°C. After drying, it was passed through a No. 30 sieve to obtain uniform granules. The obtained whole granules were placed in a plastic bag, and for every 100 parts by weight of whole granules, 57.3 parts by weight of D-mannitol (Parteck M200, Merck KGaA), 9.8 parts by weight of crospovitone (Coridon CL-F, BASF Japan Ltd.), and 2.4 parts by weight of magnesium aluminometasilicate (Neusilin, Fuji Chemical Industry Co., Ltd.) were added and mixed. To this, 1.2 parts by weight of magnesium stearate (Taihei Chemical Industry Co., Ltd.) was added and mixed to obtain granules for tableting. Using a tablet press (VELA5, Kikusui Seisakusho Co., Ltd.), the obtained granules for tableting were made into tablets to obtain uncoated tablets (tablet mass: 140 mg, tablet shape: round tablet (φ7.0 mm)).
Next, according to the formulation shown in Figure 1, PVA/PEG kraft copolymer (Coricoat IR, manufactured by BASF Japan Ltd.), polyethylene glycol (PEG6000P, Sanyo Chemical Industries, Ltd.), titanium dioxide (Wako Pure Chemical Industries, Ltd.), talc (Crown Talc, Matsumura Sangyo Co., Ltd.), and yellow iron(III) oxide (Kishi Kasei Co., Ltd.) were dissolved and dispersed in purified water to prepare a coating solution with a solid content of 8.5% by weight. Using a High Coater (HCT-MINI, Freund Industrial Co., Ltd.), the uncoated tablets obtained above were coated so that the dry coating amounted to 2.1 parts by weight per 100 parts by weight of the uncoated tablets, thereby obtaining film-coated tablets.

Example 6: Film-coated tablets
Using a mortar and pestle, istradefylline (10 g; average particle size 53.0 μm (measured using Shimadzu Corporation SALD-2200)), D-manthol (20 g, mannitol C, manufactured by Mitsubishi Corporation Life Sciences, Inc.), anhydrous calcium hydrogen phosphate (7.5 g, Fujikarin, manufactured by Fuji Chemical Industries, Inc.), yellow ferric oxide (2.5 g, Kiseki Kasei Co., Ltd.), and hydroxypropyl cellulose (1 g, HPC-L, manufactured by Nippon Soda Co., Ltd.) were mixed, and 16 g of purified water was added to the mixture to granulate it. After granulation, it was dried in a dryer at 50°C. After drying, it was passed through a No. 30 sieve to obtain uniform granules. The obtained whole granules were placed in a plastic bag, and for every 100 parts by weight of whole granules, 57.3 parts by weight of D-mannitol (Parteck M200, Merck KGaA), 9.8 parts by weight of crospovitone (Coridon CL-F, BASF Japan Ltd.), and 2.4 parts by weight of magnesium aluminometasilicate (Neusilin, Fuji Chemical Industry Co., Ltd.) were added and mixed. To this, 1.2 parts by weight of magnesium stearate (Taihei Chemical Industry Co., Ltd.) was added and mixed to obtain granules for tableting. Using a tablet press (VELA5, Kikusui Seisakusho Co., Ltd.), the obtained granules for tableting were made into tablets to obtain uncoated tablets (tablet mass: 140 mg, tablet shape: round tablet (φ7.0 mm)).
Next, according to the formulation shown in Figure 1, PVA/PEG kraft copolymer (Colicoat IR, manufactured by BASF Japan Ltd.), polyethylene glycol (PEG6000P, manufactured by Sanyo Chemical Industries, Ltd.), titanium dioxide (Wako Pure Chemical Industries, Ltd.), and talc (Crown Talc, manufactured by Matsumura Sangyo Co., Ltd.) were dissolved and dispersed in purified water to prepare a coating solution with a solid content of 8% by weight. Using a High Coater (HCT-MINI, manufactured by Freund Industrial Co., Ltd.), the uncoated tablets obtained above were coated so that the dry coating amounted to 2.1 parts by weight per 100 parts by weight of the uncoated tablets, thereby obtaining film-coated tablets.


Example 7: Uncoated Tablets
Using a mortar and pestle, istradefylline (10 g; average particle size 53.0 μm (measured using Shimadzu Corporation SALD-2200)), D-manthol (20 g, mannitol C, manufactured by Mitsubishi Corporation Life Sciences, Inc.), anhydrous calcium hydrogen phosphate (7.5 g, Fujikarin, manufactured by Fuji Chemical Industries, Inc.), yellow ferric oxide (2.5 g, Kiseki Kasei Co., Ltd.), and hydroxypropyl cellulose (1 g, HPC-L, manufactured by Nippon Soda Co., Ltd.) were mixed, and 16 g of purified water was added to the mixture to granulate it. After granulation, it was dried in a dryer at 50°C. After drying, it was passed through a No. 30 sieve to obtain uniform granules. The obtained whole granules were placed in a plastic bag, and for every 100 parts by weight of whole granules, 57.3 parts by weight of D-mannitol (Parteck M200, Merck KGaA), 9.8 parts by weight of crospovitone (Coridon CL-F, BASF Japan Ltd.), and 2.4 parts by weight of magnesium aluminometasilicate (Neusilin, Fuji Chemical Industry Co., Ltd.) were added and mixed. To this, 1.2 parts by weight of magnesium stearate (Taihei Chemical Industry Co., Ltd.) was added and mixed to obtain granules for tableting. Using a tablet press (VELA5, Kikusui Seisakusho Co., Ltd.), the obtained granules for tableting were made into tablets to obtain uncoated tablets (tablet mass: 140 mg, tablet shape: round tablet (φ7.0 mm)).

The prepared tablets were tested as follows:
Test Example 1: Stability test of film-coated tablets of Example 1 and Example 2
(method)
In accordance with the Guidelines for Photoqualitative Testing of New Active Pharmaceutical Ingredients and New Formulations (May 28, 1997) of the Trilateral International Conference on Harmonisation of Medical Devices Approval and Review (ICH), stability tests were performed on the tablets obtained in Example 1 and Tablet 2 obtained in Example 2. A D65 fluorescent lamp was used as the light source, and each tablet was exposed to a total illuminance of approximately 1,440,000 Lux·hr. After exposure, samples were taken, and the total amount of photodegradable products produced during the photodegradation process in each formulation was determined by HPLC analysis. The HPLC analysis conditions were as follows.
<HPLC analysis conditions>
Detector: UV absorbance spectrophotometer Mobile phase A: Diluted phosphoric acid (1 → 1000)
Mobile phase B: Acetonitrile apparatus, etc.: High-performance liquid chromatograph (Waters Japan), UV absorbance spectrophotometer (Waters Japan) (Results)
The amount of photodegraded products was substantially the same between the tablets of Example 1 and Example 2 (see Figure 1). This indicates that the amount of photodegraded products does not substantially change whether or not a granulation process is performed. Furthermore, it was shown that the amount of photodegraded products does not substantially change depending on the grade of D-mannitol.

Test Example 2: Dissolution Test of Film-Coated Tablets of Example 1 and Example 2 (Method)
Dissolution tests were performed on the tablets obtained in Example 1 and Tablet 2 obtained in Example 2, according to Method 2 (paddle method) described in the Dissolution Test Method of the Revised 17th Edition of the Japanese Pharmacopoeia. 900 mL of the second solution of 1.0 wt% polysorbate 80 (manufactured by Junsei Chemical Co., Ltd.) was used as the test solution, and the test was performed with a paddle rotation speed of 50 revolutions per minute. The test solution was sampled at various time points after the start of the dissolution test, and the amount of istradefylline eluted from each tablet was determined by high-performance liquid chromatography (HPLC) analysis. The HPLC analysis conditions were as follows.
<HPLC analysis conditions>
Detector: UV-absorbance spectrophotometer Mobile phase: Acetonitrile/diluted phosphoric acid (1 → 1000) mixture (3:2)
Equipment: High-performance liquid chromatograph (Hitachi High-Tech Science), ultraviolet spectrophotometer (Hitachi High-Tech Science)
(result)
At all time points from 10 minutes to 240 minutes after the start of the test, the tablets of Example 1 had a higher istradefylline dissolution rate compared to the tablets of Example 2. This demonstrated that tablets manufactured by the wet granulation method had a higher istradefylline dissolution rate compared to tablets manufactured by direct compression.

Test Example 3: Stability Test of Tablets from Examples 3 to 7 (Method)
In accordance with the Guidelines for Photoqualitative Testing of New Active Pharmaceutical Ingredients and New Formulations (May 28, 1997) of the Trilateral International Conference on Harmonisation of Technical Requirements for Approval and Evaluation of Pharmaceuticals for Human Use (ICH), stability tests were conducted on the tablets obtained in Examples 3 and beyond, their crushed products, and the granules (whole granules) before tableting. A D65 fluorescent lamp was used as the light source, and each sample was exposed to a total illuminance of approximately 1,200,000 Lux·hr. After exposure, samples were taken, and the total amount of photodegraded products produced during the photodegradation process in each sample was determined by HPLC analysis. The HPLC analysis conditions were the same as those shown in Test Example 1.
(result)
The photostability of istradefylline tablets containing D-mannitol, anhydrous calcium hydrogen phosphate, and magnesium aluminometasilicate in the tablet base remained substantially unchanged regardless of the presence or absence of a film coating layer containing titanium dioxide or talc (see Figure 1, Examples 3 and 4).
Furthermore, it was shown that tablets containing a coloring agent such as yellow iron(III) oxide in the tablet base exhibited excellent inhibitory effects on the photodegradation of istradefylline, and that if yellow iron(III) oxide was included in the tablet base, no further inhibitory effect on the photodegradation of istradefylline was observed even when a film coating containing titanium dioxide, talc, and yellow iron(III) oxide was applied (see Figure 1, Examples 5 to 7).
Furthermore, tablets containing yellow ferric oxide in the tablet coating showed the same photodegradation inhibitory effect on istradefylline even after crushing (see Figure 3, Examples 6-7). It was unexpected that the photodegradation inhibitory effect on istradefylline remained unchanged before and after crushing, despite the increased possibility that istradefylline would appear on the surface of the crushed pieces and be directly exposed to light (see Figure 3, Examples 5-7).
In Japanese Patent No. 4673745, a stability test similar to that of this test example was conducted on a tablet containing istradefylline. Therefore, the stability test results described in Patent No. 4673745 were compared with the stability test results for the tablets of Examples 4 and 7. Tablets in which D-mannitol, anhydrous calcium hydrogen phosphate, and magnesium aluminometasilicate were added instead of the crystalline cellulose that showed an inhibitory effect on the photodegradation of istradefylline in the tablets described in Patent No. 4673745 (tablets of Examples 4 and 7) showed an excellent inhibitory effect on the photodegradation of istradefylline (see Figure 2).
Furthermore, when the granules (whole granule powder) used in the tablets of Examples 4 and 7 were tested before tableting, it was found that the amount of photodegraded products was less compared to the tablets after tableting (see Figure 3). This indicates that the tableting process promotes the photodegradation of istradefylline. Therefore, it can be understood that the tableting pressure-relieving substance exerts an inhibitory effect on the photodegradation of istradefylline in tablets.

Test Example 4: Hardness Measurement Test of Tablets from Example 4 and Example 7 (Method)
Hardness was measured using a load cell type tablet hardness tester PC-30 (manufactured by Okada Seikou Co., Ltd.).

(result)
The hardness of the tablets in Example 4 and Example 7 was 82 N and 70 N, respectively. Sufficient hardness was obtained to withstand unit-dose packaging (see Figures 1 and 3).

Test Example 5: Disintegration Test of Tablets from Examples 4 and 7 (Method)
The disintegration time for each tablet in the oral cavity was measured.

(result)
The in-oral disintegration times for the tablets in Example 4 and Example 7 were 29 seconds and 36 seconds, respectively. Sufficiently fast disintegration was observed for orally disintegrating tablets (see Figures 1 and 3).

Test Example 6: Effect of lubricant on the photodegradation of istradefylline (Method)
Using a mortar and pestle, istradefylline, excipients, and lubricants were mixed in the proportions shown in Table 1 to obtain tablet granules. Using a simple tablet forming machine (HANDTAB-200, Ichihashi Seiki Co., Ltd.), the obtained tablet granules were made into tablets to obtain uncoated tablets (tablet mass: 100 mg, tablet shape: round tablet (φ6.5 mm)).

Lactose hydrate (Pharmatose 200M, manufactured by DFE Pharma)
D-mannitol (Mannit C, manufactured by Mitsubishi Corporation Foodtech)
Magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.)
Calcium stearate (manufactured by Taihei Chemical Industry Co., Ltd.)
Sodium stearyl fumarate (PRUV, manufactured by JRS Pharma)

The manufactured tablets were subjected to stability testing in accordance with the Guidelines for Photoqualitative Testing of New Active Pharmaceutical Ingredients and New Formulations (May 28, 1997) of the International Conference on Harmonisation of Technical Requirements for Approval and Evaluation of Medical Products for Human Use (ICH). A D65 fluorescent lamp was used as the light source, and each sample was exposed to a total illuminance of approximately 1,200,000 Lux·hr. After exposure, samples were taken, and the total amount of photodegradable products produced during the photodegradation process in each sample was determined by HPLC analysis. The HPLC analysis conditions were the same as those shown in Test Example 1.
(result)
When magnesium stearate was used as a lubricant and lactose monohydrate as an excipient, the amount of istradefylline dimers produced by light irradiation decreased in proportion to the content of these substances (see Figure 4).
Similarly, when magnesium stearate was used as a lubricant and D-mannitol as an excipient, the amount of istradefylline dimers produced by light irradiation decreased in proportion to their content (see Figure 5).
When calcium stearate was used as a lubricant and lactose monohydrate as an excipient, the amount of istradefylline dimers produced by light irradiation decreased at calcium stearate content of 1% and 5% by weight (see Figure 6).
Similarly, when calcium stearate was used as a lubricant and D-mannitol as an excipient, the amount of istradefylline dimers produced by light irradiation decreased at calcium stearate content of 1% and 5% by weight (see Figure 7).
When sodium stearyl fumarate was used as a lubricant and D-mannitol as an excipient, the amount of istradefylline dimers produced by light irradiation decreased at a 5% by weight content of sodium stearyl fumarate (see Figure 8).
The results above indicate that the lubricant suppresses the photodegradation of istradefylline (e.g., dimer formation) due to photoirradiation. As will be discussed later, when tablets containing istradefylline are manufactured using high tableting pressure, the amount of photodegradation products (e.g., dimers) of istradefylline increases. Therefore, although we do not intend to be bound by any particular theory, it is thought that the lubricant eased the tableting pressure and exerted an inhibitory effect on the photodegradation of istradefylline in the tablets.

Test Example 7: Effect of tablet compression pressure on the photolysis of istradefylline (Method)
Using a mortar and pestle, istradefylline 20% by weight, D-mannitol (Mannit C, manufactured by Mitsubishi Corporation Foodtech) 79% by weight, and magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.) 1% by weight were mixed to obtain tablet granules. Using a simple tablet forming machine (HANDTAB-200, Ichihashi Seiki Co., Ltd.), the obtained tablet granules were made into tablets to obtain uncoated tablets (tablet mass: 100 mg, tablet shape: round tablet (φ6.5 mm)). The tableting pressure was set to 6, 10, 15, 20, 25, or 30 kN.
Furthermore, using a mortar and pestle, istradefylline was mixed in the following proportions: 20% by weight, D-mannitol (Mannit C, manufactured by Mitsubishi Corporation Foodtech), and yellow iron(III) oxide (manufactured by Kiseki Chemical Co., Ltd.), to obtain granules for tableting. Using a simple tablet forming machine (HANDTAB-200, Ichihashi Seiki Co., Ltd.), the obtained granules were made into tablets to obtain uncoated tablets (tablet mass: 100 mg, tablet shape: round tablet (φ6.5 mm)). The tableting pressure was set to 10, 15, 25, or 30 kN.
The manufactured tablets were subjected to a photoqualitative test in the same manner as in Test Example 6.
(result)
When a mixture of istradefylline, D-mannitol, and magnesium stearate was compressed into tablets, the amount of istradefylline dimers produced by light irradiation increased in a manner dependent on the compression pressure (see Figure 9).
It was confirmed that by using a tableting pressure of 10 kN or less, the formation of dimers, which are photodegradable products of istradefylline, can be suppressed to below the threshold for degradation products in formulations requiring safety confirmation for tablets containing 20 mg of istradefylline (0.5%) (see Figure 9).
Furthermore, when a mixture of istradefylline, D-mannitol, and yellow ferric oxide was compressed into tablets, the amount of istradefylline dimers produced by light irradiation increased in a manner dependent on the tablet pressure (see Figure 10). It was confirmed that by mixing istradefylline with a coloring agent that has a photostabilizing effect and compressing it into tablets, the generation of dimers, which are photodegradable products of istradefylline, could be kept below the threshold for degradation products in a formulation requiring safety confirmation for tablets containing 20 mg of istradefylline (0.5%), even when using a tablet pressure of 30 kN (see Figure 10).

Test Example 8: Effect of excipients on the photodegradation of istradefylline (Method)
Using a mortar and pestle, istradefylline was mixed in the following proportions: 20% by weight, excipient (D-mannitol, crystalline cellulose, or anhydrous calcium hydrogen phosphate) 79% by weight, and magnesium stearate 1% by weight to obtain tablet granules. Using a simple tablet forming machine (HANDTAB-200, Ichihashi Seiki Co., Ltd.), the obtained tablet granules were made into tablets to obtain uncoated tablets (tablet mass: 100 mg, tablet shape: round tablet (φ6.5 mm)). The tableting pressure was 10 kN.
The manufactured tablets were subjected to a photoqualitative test in the same manner as in Test Example 6.
For the D-mannitol used, we used Mannit C (manufactured by Mitsubishi Corporation Foodtech); for the crystalline cellulose, we used PH-301 (manufactured by Asahi Kasei Corporation); and for the anhydrous calcium hydrogen phosphate, we used Fujikarin (manufactured by Fuji Chemical Industries Co., Ltd.).
(result)
When istradefylline and mixtures of various excipients were compressed into tablets, the formation of istradefylline photodegradation products (dimers) was almost equivalent for D-mannitol and anhydrous calcium hydrogen phosphate compared to crystalline cellulose, for which the inhibitory effect of istradefylline photodegradation products has been reported in Japanese Patent No. 4673745 (Table 2).
These results demonstrate that D-mannitol and anhydrous calcium hydrogen phosphate can be used as excipients for istradefylline-containing tablets.

The pharmaceutical composition provided by the present invention is useful for the treatment of Parkinson's disease.

Claims (10)

A compressed solid preparation comprising istradefylline, a coloring agent, and mannitol,
A solid preparation in which the coloring agent is contained in istradefylline in an amount of 1 to 50% by mass , and the proportion of mannitol in the solid preparation is 30 to 90% by weight relative to the solid preparation . The solid preparation according to claim 1, wherein the coloring agent comprises either yellow ferric oxide or ferric oxide, or both. The solid preparation according to claim 1, wherein the coloring agent contains yellow iron(III) oxide. The solid preparation according to any one of claims 1 to 3 , wherein the content of the coloring agent relative to istradefylline is 5 to 30% by mass. The solid preparation according to any one of claims 1 to 3 , wherein the content of the coloring agent relative to istradefylline is 10 to 30% by mass. A solid preparation according to any one of claims 1 to 5 , which does not contain crystalline cellulose. The solid preparation according to any one of claims 1 to 6 , further comprising a lubricant. The solid preparation according to any one of claims 1 to 7 , wherein the mixture is a granule. The solid preparation according to any one of claims 1 to 8 , wherein the solid preparation is a tablet or an orally disintegrating tablet. The solid preparation according to any one of claims 1 to 9 , wherein the solid preparation further comprises hydroxypropyl cellulose.