Perampanel solid preparation method for producing the same

Abstract

To provide a Perampanel solid preparation in which a problem of moldability is improved.SOLUTION: Perampanel solid preparation contains Perampanel anhydride and vinyl alcohol-based polymer. It is preferable that the Perampanel solid preparation include granulated materials containing Perampanel anhydride and vinyl alcohol-based polymer. The vinyl alcohol-based polymer exerts an effect as an improver of moldability. Collapsibility can be improved by further allowing the granulated materials to contain fluidizing agent.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a perampanel solid formulation and a method for producing the same. [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. In addition, solid preparations using perampanel anhydrate have also been investigated (see Patent Document 1). [Prior art documents] [Patent documents]

[0003] [Patent Document 1] JP 2023-070983 A Summary of the Invention [Problem to be solved by the invention]

[0004] In general, pharmaceuticals are required to be effective and safe as medicines, and also to have no problems in terms of production, for example, tablets must be able to be formed with a suitable hardness using a relatively small tableting pressure (pressure applied during tableting). However, as a result of further investigations, the present inventors have found that a composition containing anhydrous perampanel may require a large tableting pressure to obtain a tablet of appropriate hardness, posing a problem in terms of moldability.

[0005] The present invention has been made in consideration of the above circumstances, and an object of the present invention is to provide a perampanel solid preparation which has improved moldability. [Means for solving the problem]

[0006] As a result of extensive investigations, the present inventors have newly discovered that a vinyl alcohol polymer, which is generally used as a binder or the like in the pharmaceutical field, exhibits an effect of improving the moldability of a composition containing perampanel anhydride, and that the addition of this polymer enables the production of a perampanel solid dosage form with good moldability, which has led to the completion of the present invention.

[0007] The present invention has the following aspects. [1] A solid formulation of perampanel, comprising an anhydrous perampanel and a vinyl alcohol polymer. [2] The solid formulation of perampanel according to [1], comprising a granule containing the anhydrous perampanel and the vinyl alcohol polymer. [3] The perampanel solid formulation according to [2], wherein the granules further contain a glidant. [4] The perampanel solid formulation according to any one of [1] to [3], which is in the form of a tablet. [5] The perampanel solid formulation according to [4], which is an orally rapidly disintegrating tablet. [6] A method for producing a perampanel solid formulation from a composition containing anhydrous perampanel, comprising adding a vinyl alcohol-based polymer to the composition to improve moldability of the composition. [7] The method for producing a perampanel solid formulation according to [6], wherein the composition comprises a granule, and the granule contains the vinyl alcohol polymer. [8] The method for producing a solid formulation of perampanel according to [7], further comprising adding a glidant to the granules to improve the disintegrability of the solid formulation of perampanel. Effect of the Invention

[0008] According to the present invention, a perampanel solid formulation having improved compactability can be provided. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] The present invention will be described in detail below. The perampanel solid formulation of the present invention (hereinafter, sometimes simply referred to as a solid formulation) contains perampanel anhydride and a vinyl alcohol-based polymer. The vinyl alcohol-based polymer exhibits an effect of improving moldability in a composition containing perampanel anhydride, and by adding the vinyl alcohol-based polymer, a perampanel solid formulation with good moldability can be produced.

[0010] Any anhydrous perampanel can be used so long as it is commercially available as a pharmaceutical product.

[0011] The vinyl alcohol polymer may be any polymer having a structural unit consisting of vinyl alcohol, and one or more types may be used. For example, partially saponified polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl acetal diethylamino acetate, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, fully saponified polyvinyl alcohol, etc. are preferred, and among these, partially saponified polyvinyl alcohol and polyvinyl alcohol-polyethylene glycol graft copolymer are preferred.

[0012] There are no limitations on the partially saponified polyvinyl alcohol, so long as it can be used as an additive in the pharmaceutical field, and commercially available products can be used. From the viewpoint of the effect of improving moldability, however, it is preferable that the degree of saponification is in the range of 86.5 to 89.0 mol %, and the viscosity at 20°C when made into a 4% aqueous solution is 4.5 to 6.1 mm. 2 As such a partially saponified polyvinyl alcohol, "GOHSENOL (registered trademark) EG-05PW" available from Mitsubishi Chemical Corporation and the like can be preferably used. There are no limitations on the polyvinyl alcohol-polyethylene glycol graft copolymer, so long as it can be used as an additive in the pharmaceutical field, and any commercially available product can be used. In terms of improving moldability, however, it is preferable to use "Kollicoat (registered trademark) IR" sold by BASF Japan Ltd., which is composed of 75% polyvinyl alcohol units (craft chains) and 25% polyethylene glycol units.

[0013] As additives other than the vinyl alcohol polymer, any of additives usable in the pharmaceutical field, such as excipients, binders, disintegrants, fluidizing agents, surfactants, colorants, sweeteners, and flavors, can be contained as necessary. In particular, the use of a fluidizing agent can improve the disintegration property of the solid preparation. Examples of the fluidizing agent include light anhydrous silicon, magnesium aluminometasilicate, calcium silicate, hydrous silicon dioxide, heavy anhydrous silicic acid, talc, titanium oxide, and the like. One or more of these can be used. Among them, silicon compounds such as light anhydrous silicon, magnesium aluminometasilicate, calcium silicate, and hydrous silicon dioxide are preferred in that they can further improve the disintegration property of the solid preparation.

[0014] Specific examples of silicon compounds that can be suitably used include the following: An example of light anhydrous silicic acid is "Adsolider (registered trademark)-101" (Freund Corporation), an example of magnesium aluminometasilicate is "Neusilin (registered trademark) UFL2" (Fuji Chemical Industry Co., Ltd.), and an example of calcium silicate is "Fluorite (registered trademark) R" (Tomita Pharmaceutical Co., Ltd.).

[0015] As the excipient, one or more of D-mannitol, crystalline cellulose, lactose hydrate, anhydrous lactose, refined sucrose, potato starch, pregelatinized starch, etc. can be used as necessary, but D-mannitol, crystalline cellulose, etc. are preferred because they have low reactivity with other ingredients, excellent moldability, and can easily produce solid preparations with excellent disintegration properties.

[0016] Examples of binders include hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), polyvinylpyrrolidone, stearyl alcohol, ammonio methacrylate copolymer, polyvinyl acetal diethylaminoacetate, dextrin, and starch syrup, and one or more of these can be used as necessary.

[0017] Examples of disintegrants include croscarmellose sodium, carmellose calcium, carmellose sodium, carmellose, low-substituted hydroxypropyl cellulose, crospovidone, corn starch, sodium starch glycolate, hydroxypropyl starch, and the like, and one or more of these can be used as necessary.

[0018] Examples of the surfactant include sodium lauryl sulfate and polysorbate 80, and one or more of these can be used. Examples of coloring agents include yellow ferric oxide, ferric oxide, Food Yellow No. 4, Food Yellow No. 5, Food Red No. 2, Food Red No. 3, Food Red No. 102, and the like, and one or more of these can be used.

[0019] Examples of sweeteners include acesulfame potassium, aspartame, sucralose, thaumatin, sucrose, saccharin or a salt thereof, glycyrrhizic acid or a salt thereof, stevia or a salt thereof, and the like, and one or more of these can be used. Examples of flavorings include orange essence, orange oil, caramel, camphor, cinnamon oil, spearmint oil, strawberry essence, chocolate essence, cherry flavor, spruce oil, pine oil, peppermint oil, vanilla flavor, bitter essence, fruit flavor, peppermint essence, mixed flavor, mint flavor, 1-menthol, lemon powder, lemon oil, rose oil, and the like, and one or more of these can be used.

[0020] Other additives include lubricants (metal stearates such as magnesium stearate, calcium stearate, etc., fatty acid esters such as glycerin fatty acid esters, sucrose fatty acid esters, sodium stearyl fumarate, talc, etc.), and various coating materials (aminoalkyl methacrylate copolymer E, hydroxypropyl cellulose, hypromellose, carmellose sodium, triethyl citrate, titanium oxide, carnauba wax, etc.), and one or more of these can be used.

[0021] The solid preparation of the present invention is not limited in its form as long as it contains anhydrous perampanel and a vinyl alcohol-based polymer, and examples of the solid preparation include granular preparations (granules, dry syrups, fine granules, etc.) and tablets (immediate-release tablets, orally disintegrating tablets, etc.). However, tablets are preferred because the addition of a vinyl alcohol-based polymer has the effect of enabling tablets of appropriate hardness to be obtained with a small tableting pressure, i.e., the effect of improving moldability during tableting.

[0022] More specifically, a tablet containing a granulation containing perampanel anhydride and a vinyl alcohol-based polymer is preferred. When a tablet contains a granulation, and the granulation contains perampanel anhydride and a vinyl alcohol-based polymer, a tablet having an appropriate tablet hardness can be obtained by tableting with a small tableting pressure when a composition containing the granulation and a post-additive added as necessary is tableted. Furthermore, when the granulation contains a fluidizing agent, it is possible to increase the disintegration property of the tablet while maintaining the tablet hardness.

[0023] The content of anhydrous perampanel in the solid preparation of the present invention can be appropriately set and can be, for example, 1 to 20% by mass, preferably 1 to 10% by mass, and more preferably 1 to 5% by mass, in 100% by mass of the solid preparation. The content of the vinyl alcohol polymer can be appropriately set, but from the viewpoint of the effect of improving moldability, it is preferably 0.1 to 10 mass%, more preferably 0.1 to 5 mass%, and even more preferably 0.2 to 3 mass%, based on 100 mass% of the solid preparation. When the granules are taken as 100% by mass, the content of the vinyl alcohol polymer in the granules is, for example, preferably 0.15 to 15% by mass, more preferably 0.15 to 7% by mass, and further preferably 0.3 to 4% by mass.

[0024] When a solid preparation contains a fluidizer, the amount thereof is preferably 0.1 to 10 mass%, more preferably 0.1 to 5 mass%, and even more preferably 0.2 to 3 mass%, based on 100 mass% of the solid preparation, in terms of the effect of improving disintegrability. When the granules are taken as 100% by mass, the content of the fluidizing agent in the granules is, for example, preferably 0.15 to 15% by mass, more preferably 0.15 to 7% by mass, and further preferably 0.3 to 4% by mass.

[0025] The mass ratio of perampanel anhydride to vinyl alcohol polymer [perampanel anhydride / vinyl alcohol polymer] is preferably from 1 to 5, and more preferably from 2 to 4. Within such a range, the effect of improving moldability is sufficiently exhibited. The mass ratio of perampanel anhydride to the fluidizing agent [perampanel anhydride / fluidizing agent] is preferably 0.1 to 5, more preferably 1 to 3. Within this range, the effect of improving disintegrability is sufficiently exhibited.

[0026] The method for producing a perampanel solid formulation of the present invention is a method for producing a perampanel solid formulation from a composition containing anhydrous perampanel, and includes incorporating a vinyl alcohol-based polymer into the composition to improve the moldability of the composition. Here, it is preferred that the composition contains a granulated material, and the granulated material contains a vinyl alcohol polymer. Furthermore, by further adding a fluidizing agent to the granules, the disintegration properties of the perampanel solid preparation can be improved.

[0027] A specific manufacturing method will be described taking the case where the solid preparation is a tablet as an example. First, perampanel anhydride, a vinyl alcohol-based polymer, and a fluidizing agent and other additives added as necessary 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, stirring granulation, etc. In this case, the vinyl alcohol-based polymer may be dissolved in the solvent that is the granulation liquid. Next, additives (post-additives) are added to the obtained granules as necessary 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 necessary.

[0028] As described above, in the present invention, by adding a vinyl alcohol-based polymer to a composition containing anhydrous perampanel, the vinyl alcohol-based polymer acts as a moldability improver. As a result, for example, when the solid preparation is a tablet, an effect of improving moldability during tableting, that is, a tablet having an appropriate tablet hardness can be obtained with a small tableting pressure, can be obtained, and the problem of moldability can be solved. Furthermore, when the solid preparation contains a granulated material and a fluidizing agent is contained in the granulated material, the fluidizing agent acts as an agent for improving the disintegration property of the solid preparation, and the disintegration property of the solid preparation can be improved. EXAMPLES

[0029] The present invention will now be described in more detail with reference to examples. [Example 1] Orally disintegrating tablets were produced according to the formulation in Table 1 below. Specifically, first, the components listed in the granulation column of Table 1 were mixed except for the partially saponified polyvinyl alcohol (hereinafter, simply referred to as PVA), and a liquid (granulation liquid) in which PVA was dissolved in water was added to the mixture, and a granulation product was obtained by high-speed stirring granulation. Next, the components listed in the post-additive column of Table 1 were added to the obtained granulation product to prepare a composition for tableting, which was tableted with a rotary tableting machine (VELA5, manufactured by Kikusui Seisakusho) to obtain the orally disintegrating tablet of Example 1 (mass 200 mg, diameter 8.5 mm). During tableting, the tableting pressure was adjusted so that the tablet hardness of the resulting orally disintegrating tablets (measured according to the tablet hardness measurement method in the Reference Information of the Japanese Pharmacopoeia, 18th Edition) would be around 7 kgf (≒69 N). The tableting pressure after adjustment is shown in Table 1. The tableting pressure is expressed as the range between the minimum and maximum pressures when the rotary tablet press was operated continuously after adjustment.

[0030] [Example 2] Orally disintegrating tablets of Example 2 (mass 200 mg, diameter 8.5 mm) were obtained in the same manner as in Example 1, except that the PVA content was changed as shown in Table 1. As in Example 1, the adjusted tableting pressure is shown in Table 1.

[0031] [Examples 3 and 4] Orally disintegrating tablets (mass 200 mg, diameter 8.5 mm) of Examples 3 and 4 were obtained in the same manner as in Example 1, except that, instead of PVA, polyvinyl alcohol-polyethylene glycol graft copolymer was used in Example 3, and hydroxypropyl cellulose was used in Example 4, as shown in Table 1. As in Example 1, the adjusted tableting pressure is shown in Table 1.

[0032] [Table 1] TIFF2025009602000002.tif17170 ※1 PVA (GOHSENOL (registered trademark) EG-05PW: Mitsubishi Chemical Corporation) ※2 Polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat® IR: BASF Japan Ltd.) ※3 Hydroxypropyl cellulose (NISSO® HPC-SSL: Nippon Soda Co., Ltd.)

[0033] As shown in Table 1, when PVA was used (Examples 1 and 2) and when polyvinyl alcohol-polyethylene glycol graft copolymer was used (Example 3), orally disintegrating tablets with a tablet hardness of approximately 7 kgf could be obtained with a smaller tableting pressure than when hydroxypropyl cellulose was used (Example 4).

[0034] For the orally disintegrating tablets of Examples 1 and 2, which could be formed with a smaller tableting pressure, the disintegration time was measured for each set of six tablets using a disintegration tester (NT-400, Toyama Sangyo Co., Ltd.) in accordance with the disintegration test method of the 18th Edition of the Japanese Pharmacopoeia, but the disintegration time (average value of six tablets) was 25 seconds for Example 1 and 31 seconds for Example 2, which were slightly short of the target time of 20 seconds. Therefore, the following investigations were carried out to improve the disintegration properties.

[0035] [Examples 5-7] According to the formulation in Table 2 below, orally disintegrating tablets of each example were produced in the same manner as in Example 1, and the disintegration time of the obtained orally disintegrating tablets was measured. The method for measuring the disintegration time was as described above. The results are shown in Table 2. Table 2 also shows the tableting pressure after adjustment in the same manner as in Examples 1 to 4.

[0036] [Table 2] ※4 Light anhydrous silicic acid (Adsolider (registered trademark)-101: Freund Corporation) ※5 Magnesium aluminometasilicate (Neusilin (registered trademark) UFL2: Fuji Chemical Industry Co., Ltd.) ※6 Calcium silicate (Fluorite® R: Tomita Pharmaceutical Co., Ltd.)

[0037] As shown in Table 2, in orally disintegrating tablets containing PVA, a vinyl alcohol polymer, by adding light anhydrous silicic acid (Example 5), magnesium aluminometasilicate (Example 6), or calcium silicate (Example 7) to the granules in addition to PVA, the disintegration time could be shortened while maintaining a low tableting pressure, and disintegration properties could be improved.

Claims

1. A solid formulation of perampanel comprising anhydrous perampanel and a vinyl alcohol polymer.

2. The perampanel solid formulation according to claim 1 , comprising a granulated product containing the anhydrous perampanel and the vinyl alcohol polymer.

3. The perampanel solid formulation according to claim 2 , wherein the granulation further comprises a flow agent.

4. The perampanel solid formulation according to any one of claims 1 to 3, which is in the form of a tablet.

5. The solid formulation of claim 4, which is an orally disintegrating tablet.

6. 1. A method for producing a perampanel solid dosage form from a composition comprising perampanel anhydrate, comprising: A method for producing a perampanel solid formulation, comprising the steps of: adding a vinyl alcohol-based polymer to the composition to improve moldability of the composition.

7. The method for producing a perampanel solid formulation according to claim 6, wherein the composition comprises a granulated material, and the granulated material contains the vinyl alcohol-based polymer.

8. The method for producing a solid formulation of perampanel according to claim 7, further comprising adding a fluidizing agent to the granules to improve disintegrability of the solid formulation of perampanel.

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