Perampanel tablets

Abstract

The objective is to provide tablets containing perampanel anhydrous that are less prone to tableting failures and offer superior productivity during manufacturing. [Solution] The problem is solved by a perampanel tablet containing perampanel anhydrous and a lubricant, wherein the lubricant contains a metal stearate salt and a glycerin fatty acid ester. This prevents both binding and sticking during tableting, allowing for productive tablet manufacturing.

Description

Technical Field

[0001] The present invention relates to perampanel tablets.

Background Art

[0002] Perampanel, that is, 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one is known as an antiepileptic drug, and tablets and fine granules containing perampanel hydrate are sold. In addition, solid preparations using perampanel anhydride have also been studied (see Patent Document 1).

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0004] However, in the course of the inventor's study, when a composition for tableting was tableted in order to produce tablets containing perampanel anhydride, it was found that tableting failures such as sticking (a phenomenon in which the composition for tableting adheres to the punch of the tableting machine) and binding (a phenomenon in which scratches appear on the side surface of the produced tablets) tend to occur easily.

[0005] The present invention has been made in view of the above circumstances, and an object thereof is to provide tablets that are less likely to cause tableting failures during the production of tablets containing perampanel anhydride and have excellent productivity.

Means for Solving the Problems

[0006] As a result of diligent research, the inventors have newly discovered that by incorporating two specific types of lubricants into a tableting composition, tablets containing perampanel anhydrous can be produced successfully without causing tableting problems such as sticking or binding, thus completing the present invention.

[0007] The present invention has the following aspects. [1] A perampanel tablet containing perampanel anhydrous and a lubricant, wherein the lubricant contains a metal stearate salt and a glycerin fatty acid ester. [2] The perampanel tablet according to [1], wherein the mass ratio [metal stearate / glycerin fatty acid ester] of the metal stearate to the glycerin fatty acid ester is 0.5 to 5. [Effects of the Invention]

[0008] According to the present invention, it is possible to provide tablets that are less prone to tableting problems during the manufacture of tablets containing perampanel anhydrous, and that offer excellent productivity. [Modes for carrying out the invention]

[0009] The present invention will be described in detail below. The perampanel tablets of the present invention (hereinafter sometimes simply referred to as tablets) are tablets containing perampanel anhydrous and a lubricant, wherein the lubricant contains a metal stearate salt and a glycerin fatty acid ester. By using a combination of a metal stearate salt and a glycerin fatty acid ester as lubricants, tableting problems are less likely to occur during the manufacture of tablets containing perampanel anhydrous, and tablets can be manufactured with high productivity.

[0010] Any anhydrous perampanel available on the market as a pharmaceutical product can be used. Examples of metal stearate salts include magnesium stearate and calcium stearate, and one or more types can be used. Any glycerin fatty acid ester that is approved for use in the pharmaceutical field can be used without issue, such as the "Poem" series sold by Riken Vitamin Co., Ltd. Among these, polyglycerin fatty acid esters with 22 carbon atoms in the main constituent fatty acid (e.g., "Poem HB (product name)": triglycerin fatty acid ester (manufactured by Riken Vitamin Co., Ltd.)) can be used preferably. One or more types of glycerin fatty acid esters can be used.

[0011] Tablets may contain, as necessary, any excipients, binders, disintegrants, fluidizers, surfactants, colorants, sweeteners, flavorings, and other additives that are permitted in the pharmaceutical field. As excipients, one or more of the following can be used as needed: D-mannitol, crystalline cellulose, lactose monohydrate, anhydrous lactose, refined sucrose, potato starch, pregelatinized starch, etc. However, D-mannitol, crystalline cellulose, etc. are preferred because they have low reactivity with other components, excellent moldability, and readily produce solid formulations with good disintegration properties.

[0012] Examples of binders include hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), partially saponified polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinylpyrrolidone, stearyl alcohol, ammonia methacrylate copolymer, polyvinyl acetal diethylaminoacetate, dextrin, and corn syrup, and one or more of these can be used as needed.

[0013] Among the binders, hydroxypropyl cellulose and partially saponified polyvinyl alcohol are preferred. The partially saponified polyvinyl alcohol is not limited as long as it is usable as an additive in the pharmaceutical field; any commercially available product can be used. In terms of its ability to suppress tableting problems, a degree of saponification in the range of 86.5 to 89.0 mol% is preferred, and the viscosity at 20°C when prepared as a 4% aqueous solution should be 4.5 to 6.1 mm². 2A polyvinyl alcohol partially saponified product in the range of / s is preferred. As such a partially saponified polyvinyl alcohol, products such as "Gosenol (registered trademark) EG-05PW," sold by Mitsubishi Chemical Corporation, can be preferably used.

[0014] Examples of disintegrants include croscarmellose sodium, carmellose calcium, carmellose sodium, carmellose, low-substituted hydroxypropyl cellulose, crospovidone, corn starch, sodium starch glycolate, and hydroxypropyl starch, and one or more of these can be used as needed.

[0015] Examples of fluidizing agents include light anhydrous silicon, magnesium aluminometasilicate, calcium silicate, hydrated silicon dioxide, heavy anhydrous silicic acid, talc, and titanium dioxide. One or more of these can be used, but silicon compounds such as light anhydrous silicon, magnesium aluminometasilicate, calcium silicate, and hydrated silicon dioxide are preferred because they can further improve the disintegration properties of the tablets. Specific examples of silicon compounds that can be suitably used include the following: Examples of light anhydrous silicic acid include "Adsolider (registered trademark)-101" (Freund Industrial Co., Ltd.), examples of magnesium aluminometasilicate include "Neusilin (registered trademark) UFL2" (Fuji Chemical Industry Co., Ltd.), and examples of calcium silicate include "Fluorite (registered trademark) R" (Tomita Pharmaceutical Co., Ltd.).

[0016] Examples of surfactants include sodium lauryl sulfate and polysorbate 80, and one or more of these can be used. Examples of coloring agents include yellow iron(III) oxide, iron(III) oxide, 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, and one or more of these may 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, l-menthol, lemon powder, lemon oil, rose oil, etc., and one or more of these may be used.

[0018] Other additives include various materials for tablet coating (such as aminoalkyl methacrylate copolymer E, hydroxypropyl cellulose, hypromellose, carmellose sodium, triethyl citrate, titanium dioxide, and carnauba wax), and one or more of these may be used. Furthermore, while there is no restriction on using other lubricants such as sucrose fatty acid esters, sodium stearyl fumarate, talc, etc., in addition to metal stearate and glycerin fatty acid esters, sufficient suppression of tableting disorders can be obtained by using only metal stearate and glycerin fatty acid esters.

[0019] The tablets of the present invention are not particularly limited as long as they are formed by containing perampanel anhydrous and a lubricant containing a metal stearate salt and a glycerin fatty acid ester. Specifically, tablets are preferred that are formed by compressing a composition for tableting which is a mixture of granules consisting of perampanel anhydrous and additives such as excipients, disintegrants, and binders used as needed, and additives added to the granules (post-additives). It is preferable that the metal stearate salt and glycerin fatty acid ester are included in the post-additives in order to provide tablets that are less prone to tableting problems and have better productivity. Furthermore, it is preferable that both the excipient and the disintegrant are included in both the granules and the post-additives. Examples of the tablet form may include immediate-release tablets, orally disintegrating tablets, etc., and there is no particular limitation.

[0020] The content of perampanel anhydride in the tablets of the present invention can be set as appropriate, and in 100% by mass of the tablets, for example, it can be 1 to 20% by mass, preferably 1 to 10% by mass, more preferably 1 to 5% by mass. The total content of the metal stearate and glycerin fatty acid ester added as lubricants can be, for example, 0.1 to 10% by mass in 100% by mass of the tablets, preferably 0.5 to 5% by mass, more preferably 0.5 to 3% by mass, and still more preferably 0.5 to 1.5% by mass. Also, the mass ratio [metal stearate / glycerin fatty acid ester] of the metal stearate and glycerin fatty acid ester in the tablets is, for example, 0.5 to 5, preferably 0.5 to 3, more preferably 0.5 to 2, and still more preferably 0.5 to 1.5.

[0021] As described above, from the viewpoint of providing tablets that are less likely to cause tableting problems and have excellent productivity, it is preferable that the tablets are those in which the granulated product and the post-additive containing the metal stearate and glycerin fatty acid ester are mixed and then tableted. Here, the mass ratio [granulated product / post-additive] of the granulated product and the post-additive is, for example, 1 to 5, preferably 2 to 4, more preferably 2 to 3. In the tablets containing perampanel anhydride, it is preferable in that by containing both the metal stearate and glycerin fatty acid ester in the above contents and ratios, etc., it is possible to provide tablets that are less likely to cause tableting problems and have excellent productivity.

[0022] The content of the optionally used additive can be set as appropriate. For example, the binder is preferably 0.1 to 10% by mass in 100% by mass of the tablets, more preferably 0.1 to 5% by mass, and still more preferably 0.2 to 3% by mass. The binder is preferably contained in the granules, and when the granules are considered as 100% by mass, the binder content in the granules is preferably, for example, 0.15 to 15% by mass, more preferably 0.15 to 7% by mass, and even more preferably 0.3 to 4% by mass.

[0023] The mass ratio of perampanel anhydrous to binder [perampanel anhydrous / binder] is preferably 1 to 5, and more preferably 2 to 4. Within this range, tableting problems tend to be suppressed.

[0024] The perampanel tablets of the present invention can be manufactured, for example, as follows. First, anhydrous perampanel and additives as needed are mixed to form a granulation composition. A solvent such as purified water is then added to the granulation composition as a granulation liquid, and granulation is carried out using known methods such as fluidized bed granulation, rolling fluidized bed granulation, or agitated granulation. In this case, a solution of additives such as binders dissolved in purified water may be used as the granulation liquid. Next, a lubricant containing a metal stearate salt and a glycerin fatty acid ester, along with any other additives, is added to the obtained granules to form a tableting composition, which is then compressed into tablets using a tablet press. A coating layer may be formed on the surface of the tablets obtained by compression, if necessary.

[0025] As described above, the present invention relates to perampanel tablets containing perampanel anhydrous and a lubricant, wherein the lubricant contains a metal stearate salt and a glycerin fatty acid ester. Therefore, the metal stearate salt and the glycerin fatty acid ester act synergistically as tableting improvers, allowing for productive manufacturing without causing tableting problems such as sticking or binding. [Examples]

[0026] The present invention will be specifically described below with reference to examples. [Examples 1-3] Orally disintegrating tablets were manufactured according to the formulation shown in Table 1 below. Specifically, first, all components listed in the granule column of Table 1, except for hydroxypropylcellulose (the binder), were mixed. To this mixture, a solution of hydroxypropylcellulose dissolved in water (granulation solution) was added, and granules were obtained by high-speed stirring granulation. Next, the components listed in the post-additive column of Table 1 were added to the obtained granules to create a tablet composition, which was then compressed into orally disintegrating tablets (100 mg mass, 6.5 mm diameter) of Examples 1-3 using a rotary tablet press (VELA5, manufactured by Kikusui Seisakusho). During this process, the presence or absence of tableting defects (sticking and binding) was checked as follows.

[0027] <Sticking> After continuously compressing 800 tablets (200 tablets / punch), if no residue of the composition was observed on the punch, it was recorded as "none," and if residue was observed, it was recorded as "present." This was recorded in Table 1. <binding> Tablets were compressed continuously up to 800 tablets (200 tablets / punch) and if no tablets with scratches on the side were found, the result was recorded as "none"; if scratches were found, the result was recorded as "present," and this was shown in Table 1.

[0028] [Example 4] Orally disintegrating tablets (100 mg in mass, 6.5 mm in diameter) were continuously produced in the same manner as in Example 1, except that partially saponified polyvinyl alcohol (hereinafter referred to as PVA) was used instead of hydroxypropyl cellulose, and the presence or absence of tableting defects (sticking and binding) was checked.

[0029] [Table 1]

[0030] As shown in Table 1, when magnesium stearate and glycerin fatty acid ester were used in combination as lubricants (Examples 1 and 4), neither binding nor sticking occurred, and tablets could be manufactured with high productivity.

Claims

1. A perampanel tablet containing perampanel anhydrous and a lubricant, A perampanel tablet wherein the lubricant contains a metal stearate salt and a glycerin fatty acid ester.

2. The perampanel tablet according to claim 1, wherein the mass ratio [metal stearate / glycerin fatty acid ester] of the metal stearate to the glycerin fatty acid ester is 0.5 to 5.

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