Perampanel solid preparation

Abstract

To provide a perampanel solid preparation having superior photostability.SOLUTION: The problem is solved by a perampanel solid preparation, which contains perampanel anhydrate and partially saponified polyvinyl alcohol. As the partially saponified polyvinyl alcohol, one having a saponification degree of 85.0-89.0 mol% is preferred, in view of improving photostability. Solid preparations include, for example, granule formulations and tablets.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a solid formulation of perampanel. [Background technology]

[0002] Perampanel, i.e., 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one, is known as an antiepileptic drug, and tablets and granules containing perampanel hydrate are commercially available. Solid formulations using perampanel anhydrate have also been investigated (see Patent Document 1). [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Japanese Patent Publication No. 2023-070983 Summary of the Invention [Problem to be solved by the invention]

[0004] The present inventors have conducted studies on solid preparations using anhydrous perampanel and have found that compositions containing anhydrous perampanel tend to have insufficient photostability.

[0005] The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a perampanel solid formulation that is excellent in photostability. [Means for solving the problem]

[0006] As a result of intensive research, the present inventors have found that by adding a partially saponified polyvinyl alcohol as a binder, it is possible to provide a perampanel solid formulation that is excellent in photostability and that is inhibited from increasing related substances due to light, and have thus completed the present invention.

[0007] The present invention has the following aspects. 〔1〕A perampanel solid preparation containing perampanel anhydride and a partially saponified polyvinyl alcohol. 〔2〕The perampanel solid preparation according to 〔1〕, comprising a granulated product containing the perampanel anhydride and the partially saponified polyvinyl alcohol. 〔3〕The perampanel solid preparation according to 〔2〕, which is a granular preparation. 〔4〕The perampanel solid preparation according to 〔2〕, which is a tablet.

Advantages of the Invention

[0008] According to the present invention, a perampanel solid preparation excellent in light stability can be provided.

Modes for Carrying Out the Invention

[0009] Hereinafter, the present invention will be described in detail. The perampanel solid preparation of the present invention (hereinafter, may be simply referred to as a solid preparation) contains perampanel anhydride and a partially saponified polyvinyl alcohol. When a partially saponified polyvinyl alcohol is added, the perampanel solid preparation is excellent in light stability.

[0010] As the perampanel anhydride, any one can be used as long as it is available on the market as a pharmaceutical.

[0011] There is no limitation on the partially saponified polyvinyl alcohol as long as it can be used as an additive in the pharmaceutical field, and those available on the market can be used. However, in terms of improving light stability, those having a saponification degree in the range of 85.0 to 89.0 mol% are preferable. Further, when it is made into a 4% aqueous solution, the viscosity at 20 °C is preferably in the range of 4.5 to 6.1 mm 2 / s. As the partially saponified polyvinyl alcohol having a saponification degree and viscosity in the above ranges, "Gosenol (registered trademark) EG-05PW" sold by Mitsubishi Chemical Corporation, "PE-05JPS" sold by Nippon Vinyl Acetate-Poval Co., Ltd., etc. can be preferably used.

[0012] As additives other than the partially saponified polyvinyl alcohol, any additives such as excipients, binders, disintegrants, fluidizing agents, surfactants, coloring agents, sweeteners, flavoring agents, and fragrances that can be used in the pharmaceutical field can be contained as necessary.

[0013] As the excipient, one or more of D-mannitol, crystalline cellulose, lactose hydrate, anhydrous lactose, refined sugar, potato starch, pregelatinized starch, etc. can be used as necessary. However, D-mannitol is preferable in terms of low reactivity with other components, excellent moldability, and ease of obtaining a solid preparation with excellent disintegrability. Particularly when the solid preparation is a granular preparation, D-mannitol is also preferable in terms of mouthfeel. For the same reason, crystalline cellulose is also preferable.

[0014] As the binder, in addition to the above-mentioned partially saponified polyvinyl alcohol, those that can be used as binders in the pharmaceutical field (for example, hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), polyvinylpyrrolidone, stearyl alcohol, ammonio methacrylate copolymer, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl acetal diethylaminoacetate, dextrin, starch paste, etc.) can also be used as necessary. However, from the viewpoint of light stability, it is preferable to use only the partially saponified polyvinyl alcohol.

[0015] Examples of the disintegrant include croscarmellose sodium, carmellose calcium, carmellose sodium, carmellose, low-substituted hydroxypropyl cellulose, crospovidone, corn starch, sodium starch glycolate, hydroxypropyl starch, etc., and one or more of these can be used as necessary.

[0016] Examples of the surfactant include sodium lauryl sulfate, polysorbate 80, etc., and one or more of these can be used. Examples of colorants include yellow iron oxide (III), iron oxide (III), Food Yellow No. 4, Food Yellow No. 5, Food Red No. 2, Food Red No. 3, Food Red No. 102, etc., and one or more of these can be used.

[0017] Examples of sweeteners include acesulfame potassium, aspartame, sucralose, thaumatin, sucrose, saccharin or its salts, glycyrrhizic acid or its salts, stevia or its salts, etc., and one or more of these can be used. As a flavoring agent, erythritol can preferably be used in that it can impart a cooling sensation and a pleasant aftertaste. Examples of fragrances include orange essence, orange oil, caramel, camphor, cinnamon oil, spearmint oil, strawberry essence, chocolate essence, cherry flavor, thuja oil, pine oil, peppermint oil, vanilla flavor, bitter essence, fruit flavor, peppermint essence, mixed flavor, mint flavor, l-menthol, lemon powder, lemon oil, rose oil, etc., and one or more of these can be used.

[0018] Examples of fluidizing agents include light anhydrous silica, magnesium aluminometasilicate, calcium silicate, hydrous silicon dioxide, heavy anhydrous silicic acid, talc, etc., and one or more of these can be used, with light anhydrous silica being preferred.

[0019] Examples of other additives include lubricants (metal stearates such as magnesium stearate and calcium stearate, fatty acid esters such as glycerin fatty acid esters and sucrose fatty acid esters, sodium stearyl fumarate, talc, etc.) and various coating materials (aminoalkyl methacrylate copolymer E, hydroxypropyl cellulose, hypromellose, sodium carboxymethylcellulose, triethyl citrate, titanium oxide, carnauba wax, etc.), as required. Titanium oxide is preferably added from the viewpoint of light stability, and is not limited to being added as a coating material, and may also be added to parts other than the coating. One or more of these additives can also be used.

[0020] The solid preparation of the present invention has no limitation in its form as long as it contains perampanel anhydride and a partially saponified polyvinyl alcohol. Examples include granular preparations (granules, dry syrups, fine granules, etc.), tablets (immediate-release tablets, orally disintegrating tablets, etc.). However, since granular preparations have a larger surface area than tablets and tend to be more affected by light, the present invention is particularly effective when it is a granular preparation.

[0021] The contents of perampanel anhydride and the partially saponified polyvinyl alcohol in the solid preparation of the present invention can be appropriately set according to the dosage form of the solid preparation and the like. The mass ratio of these [partially saponified polyvinyl alcohol / perampanel anhydride] is preferably 0.1 to 12, more preferably 0.1 to 10, and even more preferably 0.2 to 8. When the solid preparation is particularly a granular preparation, 1 to 12 is preferable, 2 to 10 is more preferable, and 4 to 8 is even more preferable. When the solid preparation is particularly a tablet, 0.1 to 2 is preferable, 0.2 to 1 is more preferable, and 0.25 to 0.5 is even more preferable. Within the above range, while exerting the function as a binder, the light stability of the solid preparation can be improved.

[0022] The content of perampanel anhydride in 100% by mass of the solid preparation can be, for example, 0.1 to 10% by mass, preferably 0.1 to 5% by mass, and more preferably 0.1 to 3% by mass. The content of the partially saponified polyvinyl alcohol can be appropriately set in consideration of light stability according to the dosage form of the solid preparation and the like. In 100% by mass of the solid preparation, 0.1 to 20% by mass is preferable, more preferably 0.2 to 10% by mass, and even more preferably 0.2 to 8% by mass. When the solid preparation is particularly a granular preparation, in 100% by mass of the solid preparation, 0.1 to 20% by mass is preferable, more preferably 2 to 10% by mass, and even more preferably 4 to 8% by mass. When the solid preparation is particularly a tablet, in 100% by mass of the solid preparation, 0.1 to 10% by mass is preferable, more preferably 0.2 to 5% by mass, and even more preferably 0.2 to 3% by mass.

[0023] The content of the excipient is preferably 80 to 95% by mass of 100% by mass of the solid preparation, but can be appropriately set depending on the dosage form of the solid preparation, etc. When the solid preparation is particularly a granular preparation, the content is preferably 85 to 95% by mass, more preferably 90 to 95% by mass of 100% by mass of the solid preparation. When the solid preparation is particularly a tablet, the content is preferably 80 to 90% by mass, more preferably 80 to 85% by mass of 100% by mass of the solid preparation. When the solid preparation of the present invention contains a flavoring agent such as erythritol, it is preferable that the total amount of the excipient and flavoring agent be within the above-mentioned preferred range. That is, the total content of the excipient and flavoring agent is preferably 80 to 95% by mass of 100% by mass of the solid preparation. The total content of the excipient and flavoring agent can also be appropriately set depending on the dosage form of the solid preparation, and when the solid preparation is particularly a granular preparation, it is preferably 85 to 95% by mass, more preferably 90 to 95% by mass of 100% by mass of the solid preparation. When the solid preparation is particularly a tablet, it is preferably 80 to 90% by mass, more preferably 80 to 85% by mass of 100% by mass of the solid preparation. The mass ratio of the excipient to the flavoring agent [flavoring agent / excipient] is preferably 0.01 to 0.2, more preferably 0.03 to 0.15, and even more preferably 0.10 to 0.15.

[0024] Other additives can also be appropriately selected depending on the dosage form of the solid preparation. For example, in the case of a granular preparation, in addition to the granules, a fluidizer such as light anhydrous silicic acid may be separately contained for the purpose of improving the fluidity of the granules or preventing adhesion. In this case, the content of the fluidizer is preferably 3% by mass or less, more preferably 2% by mass or less, and even more preferably 1% by mass or less, based on 100% by mass of the solid preparation. A flavoring can also be preferably added. In this case, the content of the flavoring is preferably 1% by mass or less, based on 100% by mass of the solid preparation.

[0025] When the solid formulation of perampanel of the present invention is a granular formulation, it can be produced, for example, by the following method. First, anhydrous perampanel, partially saponified polyvinyl alcohol, and other additives added as needed are mixed to prepare a composition for granulation, and a solvent such as purified water is added as a granulation liquid to the composition for granulation, followed by granulation by a known method such as fluidized bed granulation, tumbling fluidized bed granulation, agitation granulation, etc. In this case, a portion of the composition for granulation, such as the partially saponified polyvinyl alcohol, may be dissolved in the solvent that is the granulation liquid. Next, a fluidizing agent, flavoring agent, etc. can be added to the obtained granules as needed to obtain a granular preparation, which is one embodiment of the solid preparation of the present invention. When the perampanel solid formulation of the present invention is a tablet, a granulated product (granules) is first produced in the same manner as in the production of a granular formulation. Then, additives (post-additives) are added to the resulting granulated product (granules) as needed to prepare a composition for tableting, which is then tableted using a tablet press. A coating layer may be formed on the surface of the tablets obtained by tableting, as needed.

[0026] As described above, the solid preparation of the present invention contains anhydrous perampanel and partially saponified polyvinyl alcohol, and therefore the partially saponified polyvinyl alcohol exhibits the effect of improving photostability, making it possible to provide a solid preparation with excellent photostability. [Example]

[0027] The present invention will now be described in more detail with reference to examples. [Examples 1-4] A granular preparation was produced according to the formulation in Table 1 below. Specifically, first, perampanel anhydrate and D-mannitol were mixed among the ingredients listed in the granulated product column of Table 1, and the remaining ingredients listed in the granulated product column of Table 1 were added to purified water and sprayed onto the resulting mixture to perform fluidized bed granulation to obtain a granulated product (granules). The mixture was then passed through a 30-mesh screen for sizing, and the ingredients listed in the final blending column were mixed in to obtain a granulated preparation containing each ingredient in the proportions shown in Table 1. The resulting granulated preparation was subjected to a photostability test using the following method.

[0028] <Photostability test> In an open system, each granular preparation was continuously irradiated with light of 3000 lx, and the total amount of related substances at the time when the integrated irradiation dose from the start of irradiation reached 600,000 lx·hr and 1,200,000 lx·hr was measured, and the increase amount from the total amount of related substances before irradiation was calculated. The results are shown in Table 1. Specifically, 0.2 g of the granular preparation was dissolved in 15 mL of a 7:3 mixed solution of potassium dihydrogen phosphate solution at pH 4.6 and acetonitrile. The obtained solution was sonicated for 10 minutes and made up to 25 mL, and then filtered through a filter, and the filtrate was used as a sample solution. This was analyzed by an automatic analysis method using high performance liquid chromatography. The numerical value of the total amount of related substances is expressed as a percentage of the ratio of the sum of the peak areas of a plurality of observed related substances to the peak area derived from the perampanel.

[0029]

Table 1

[0030] As shown in Table 1, the solid preparations of Example 1 and Example 2 containing partially saponified polyvinyl alcohol (also simply referred to as PVA) had the increase of related substances suppressed by light irradiation and had good light stability.

[0031] [Example 5, 6] According to the formulation in Table 2 below, orally disintegrating tablets were manufactured. Specifically, first, among the components described in the granulated product column of Table 2, the components other than PVA were mixed, and a solution in which PVA was dissolved in water (granulating solution) was added thereto, and a granulated product was obtained by a high-speed stirring granulation method. Then, the components described in the post-additive column of Table 2 were added to the obtained granulated product to obtain a composition for tableting, and this was tableted with a rotary tablet press (manufactured by Kikusui Seisakusho, VELA5) to obtain the orally disintegrating tablets of Example 5 and 6 (mass 200 mg, diameter 8.0 mm). For the obtained orally disintegrating tablets, a photo-stability test was conducted by the above method (however, instead of adding 0.2 g of the granular preparation to 15 mL of the mixed solution and making up to 25 mL, 1 orally disintegrating tablet was added to 35 mL of the mixed solution and made up to 50 mL. Also, the measurement was performed only when the integrated irradiation dose reached 1,200,000 lx·hr.).

[0032] [Examples 7, 8] As shown in Table 2, except that a polyvinyl alcohol - polyethylene glycol graft copolymer was used in Example 7 and hydroxypropyl cellulose was used in Example 8 instead of PVA, orally disintegrating tablets of Examples 7 and 8 (mass 200 mg, diameter 8.0 mm) were obtained in the same manner as in Example 5, and a photo-stability test was conducted in the same manner.

[0033]

Table 2

[0034] As shown in Table 2, the solid preparations of Examples 5 and 6 containing PVA had an increase in related substances suppressed by light irradiation and had good photo-stability.

[0035] [Examples 9, 10] Granular preparations were produced in the same manner as in Example 1, except that the formulation was changed as shown in Table 3. However, erythritol was added by mixing with perampanel anhydride and D-mannitol. When a photo-stability test was conducted in the same manner as in Example 1, the granular preparations of Examples 9 and 10 also had an increase in related substances suppressed by light irradiation and had good photo-stability.

[0036]

Table 3

[0037] Also, when 7 panelists held the solid preparations (granular preparations) of Examples 2 and 10 in their mouths for sensory evaluation, in all panelists, the solid preparation of Example 10 containing erythritol as a flavoring agent was evaluated to have a cool feeling and a good aftertaste of sweetness.

Claims

1. A perampanel solid preparation containing perampanel anhydride and a partially saponified polyvinyl alcohol.

2. The perampanel solid preparation according to claim 1, comprising a granulated product containing the perampanel anhydride and the partially saponified polyvinyl alcohol.

3. The perampanel solid preparation according to claim 2, which is a granular preparation.

4. The perampanel solid preparation according to claim 2, which is a tablet.

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