Pharmaceutical composition containing perampanel anhydrous and method for producing the same

Abstract

The objective is to improve the elution properties of perampanel anhydrous. [Solution] The above problem is solved by a pharmaceutical composition comprising perampanel anhydrous and a pharmaceutically acceptable cellulose derivative and / or polyvinylpyrrolidone.

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition containing perampanel anhydrous and a method for producing the same. The present invention relates to a method for producing tablets containing perampanel anhydrous. The present invention relates to a method for improving the dissolution properties of perampanel anhydrous in a pharmaceutical composition containing perampanel anhydrous. [Background technology]

[0002] Perampanel is a compound represented by the following formula (I), and its chemical name is 2-(6'-oxo-1'-phenyl-1',6'-dihydro[2,3'-bipyridine]-5'-yl)benzonitrile.

[0003] [ka]

[0004] For example, Patent Document 1 describes perampanel as a compound that is a selective, non-competitive antagonist of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) type glutamate receptors, which are mainly present in the postsynaptic membrane, and exerts antiepileptic effects. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] International Publication No. 2001 / 096308 [Overview of the Initiative] [Problems that the invention aims to solve]

[0006] Currently available perampanel formulations contain perampanel hydrate as the active ingredient. The present inventors manufactured tablets containing perampanel anhydrous as the active ingredient, but the dissolution of the active ingredient from these tablets was unsatisfactory. This was due to the lower solubility of perampanel anhydrous compared to perampanel hydrate. Therefore, the present invention aims to improve the dissolution of perampanel anhydrous in pharmaceutical compositions. [Means for solving the problem]

[0007] As a result of diligent research, the inventors have discovered that the elution properties of perampanel anhydride in pharmaceutical compositions can be improved by using cellulose derivatives and / or polyvinylpyrrolidone, and have completed the present invention. Accordingly, the present invention provides a pharmaceutical composition comprising perampanel anhydride and a pharmaceutically acceptable cellulose derivative and / or polyvinylpyrrolidone.

[0008] The present invention provides a method for producing a pharmaceutical composition containing perampanel anhydride, comprising the step of mixing perampanel anhydride with a pharmaceutically acceptable cellulose derivative and / or polyvinylpyrrolidone.

[0009] The present invention provides a method for producing tablets containing perampanel anhydrous, comprising the steps of: mixing perampanel anhydrous with a pharmaceutically acceptable cellulose derivative and / or polyvinylpyrrolidone to obtain a mixture; granulating the mixture; and compressing the granules to obtain tablets.

[0010] The present invention provides a method for improving the elution properties of perampanel anhydride in a pharmaceutical composition containing perampanel anhydride, comprising including the inclusion of a pharmaceutically acceptable cellulose derivative and / or polyvinylpyrrolidone in the pharmaceutical composition containing perampanel anhydride. [Effects of the Invention]

[0011] According to the present invention, a pharmaceutical composition in which the solubility of perampanel anhydrous is improved, and a method for producing the same are provided.

Brief Description of the Drawings

[0012] [Figure 1] These are the results of the dissolution tests of the tablets of Comparative Example 1 and Examples 1 to 6. [Figure 2] These are the results of the dissolution tests of the tablets of Comparative Example 1 and Examples 7 to 9. [Figure 3] These are the results of the dissolution tests of the tablets of Comparative Example 1 and Examples 10 to 12.

Modes for Carrying Out the Invention

[0013] (Pharmaceutical Composition Containing Perampanel Anhydrate) The pharmaceutical composition of this embodiment contains perampanel anhydrate as an active ingredient. The shape of perampanel anhydrate is not particularly limited, and it may be any shape such as powder or granules. The pharmaceutical composition of this embodiment substantially does not contain perampanel hydrate. "Substantially not contained" means that even if perampanel hydrate is contained in the pharmaceutical composition, it is in a small amount and perampanel hydrate is not actively added. Examples of cases where perampanel hydrate is contained include, for example, when it is mixed in trace amounts as an impurity, or when it is generated in trace amounts due to some chemical reaction or the like.

[0014] The particle size of perampanel anhydrate is not particularly limited, but the particle size (D

[0014] , 50 , , , , 90 , , 10 , , ) of the powder or crystal of perampanel anhydrate is 0.1 μm or more and 3.0 μm or less, the particle size (D 50 ) is 3.0 μm or more and 9.0 μm or less, and the particle size (D 90 ) is 9.0 μm or more and 50.0 μm or less. The particle size of perampanel anhydrate is based on the volume-based particle size distribution measured using a laser diffraction / scattering particle size distribution measuring device. Examples of the laser diffraction / scattering particle size distribution measuring device include, for example, "Aerotrak LDSA-SPR" of Microtrac Bell Co., Ltd., "Mastersizer 3000" of Malvern Panalytical, etc.

[0015] The lower limit of the particle diameter (D 10 ) of the powder or crystal of perampanel anhydrate is, for example, 0.1 μm, 0.2 μm, 0.3 μm, 0.4 μm, 0.5 μm, 0.6 μm, 0.7 μm. The particle diameter (D 10 ) of the powder or crystal of perampanel anhydrate has an upper limit of, for example, 3.0 μm, 2.8 μm, 2.6 μm, 2.5 μm, 2.3 μm, 2.2 μm, 2.1 μm, 2.0 μm, 1.8 μm, 1.6 μm, 1.5 μm.

[0016] The lower limit of the particle diameter (D 50 ) of the powder or crystal of perampanel anhydrate is, for example, 3.0 μm, 3.1 μm, 3.2 μm, 3.3 μm, 3.4 μm, 3.5 μm. The particle diameter (D 50 ) of the powder or crystal of perampanel anhydrate has an upper limit of, for example, 9.0 μm, 8.5 μm, 8.0 μm, 7.5 μm, 7.0 μm, 6.​​​​​​​​​​​The perampanel anhydrous content in the pharmaceutical composition is 0.1% by mass or more and 30% by mass or less of the total mass of the pharmaceutical composition. The lower limit of the perampanel anhydrous content is, for example, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 0.95%, and 0.99% by mass of the total mass of the pharmaceutical composition. The upper limit of the perampanel anhydrous content is, for example, 30%, 25%, 20%, 15%, and 10% by mass of the total mass of the pharmaceutical composition.

[0019] The pharmaceutical composition of this embodiment contains a cellulose derivative and / or polyvinylpyrrolidone as a binder. By using a cellulose derivative and / or polyvinylpyrrolidone as a binder, the elution properties of perampanel anhydrous can be improved.

[0020] The cellulose derivative is not particularly limited as long as it is a pharmaceutically acceptable cellulose derivative, but examples include compounds in which some of the hydrogen atoms of the hydroxyl group of cellulose are replaced with methyl groups, ethyl groups, propyl groups, hydroxymethyl groups, hydroxyethyl groups, hydroxypropyl groups, etc. Examples include hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl cellulose, and carboxymethylcellulose. Of these, hydroxypropyl methylcellulose, hydroxyethyl cellulose, and hydroxypropyl cellulose are preferred, and hydroxypropyl cellulose is more preferred. The cellulose derivative may be one type or a combination of two or more types.

[0021] The degree of substitution, molecular weight, and viscosity of the cellulose derivative are not particularly limited, but the degree of substitution is preferably in the range of 10% to 90%, and more preferably in the range of 20% to 80%.

[0022] The molecular weight is preferably in the range of 10,000 to 500,000, more preferably in the range of 10,000 to 200,000, and particularly preferably in the range of 20,000 to 150,000. In this specification, the molecular weight is the weight-average molecular weight measured by gel permeation chromatography (GPC).

[0023] The viscosity is preferably 1 mPa·s to 100 mPa·s, more preferably 1 mPa·s to 50 mPa·s, and particularly preferably 1 mPa·s to 10 mPa·s. Herein, in this specification, viscosity is the value obtained by measuring the viscosity of a 1% by mass solution of the compound to be measured (e.g., hydroxypropyl cellulose) based on the rotational viscometer method described in the Japanese Pharmacopoeia.

[0024] Examples of hydroxypropyl cellulose include HPC-SSL and HPC-SL manufactured by Nippon Soda Co., Ltd.

[0025] Polyvinylpyrrolidone is a nonionic, water-soluble polymer compound formed by the polymerization of N-vinyl-2-pyrrolidone. The molecular weight of polyvinylpyrrolidone is not particularly limited, but it is preferably in the range of 10,000 to 500,000, more preferably in the range of 10,000 to 200,000, and most preferably in the range of 20,000 to 150,000.

[0026] The K value (viscosity characteristic value) of polyvinylpyrrolidone is not particularly limited, but is preferably in the range of 1 to 70, and more preferably in the range of 10 to 50. Here, the K value is the relative viscosity η of the polyvinylpyrrolidone aqueous solution with respect to water, as measured by a capillary viscometer. rel (25℃) is calculated using Fickencher's formula below.

[0027]

number

[0028] Examples of polyvinylpyrrolidone include Coridon® 30 and Coridon® 25, manufactured by BASF Japan Ltd. One type of polyvinylpyrrolidone may be used, or a combination of two or more types may be used.

[0029] The content of cellulose derivatives or polyvinylpyrrolidone in the pharmaceutical composition is not particularly limited, but is preferably 0.1% to 20% by mass of the total mass of the pharmaceutical composition, more preferably 0.3% to 15% by mass, and particularly preferably 0.5% to 12% by mass.

[0030] The lower limit of the cellulose derivative content in the pharmaceutical composition is, for example, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.9%, and 1.0% by mass of the total mass of the pharmaceutical composition. The upper limit of the cellulose derivative content is, for example, 30%, 25%, 20%, 15%, and 10% by mass of the total mass of the pharmaceutical composition.

[0031] The lower limit of the polyvinylpyrrolidone content in a pharmaceutical composition is, for example, 0.1% by mass, 0.2% by mass, 0.3% by mass, 0.4% by mass, 0.5% by mass, 0.9% by mass, 1.0% by mass, 1.1% by mass, 1.2% by mass, 1.5% by mass, 2.0% by mass, 2.1% by mass, 2.2% by mass, 2.5% by mass, 3.0% by mass, 4.0% by mass, 5.0% by mass, 6.0% by mass, 6.5% by mass, 7.0% by mass, 7.5% by mass, and 8.0% by mass of the total mass of the pharmaceutical composition.

[0032] The upper limits for the polyvinylpyrrolidone content are, for example, 30%, 25%, 20%, 15%, and 10% by mass of the total mass of the pharmaceutical composition. When the polyvinylpyrrolidone content is 3.0% by mass or more, particularly excellent elution properties are imparted to the pharmaceutical composition using perampanel anhydrous.

[0033] The pharmaceutical composition of this embodiment may optionally contain pharmaceutically acceptable pharmaceutical additives. Examples of such pharmaceutical additives include coating agents, excipients, stabilizers, lubricants, disintegrants, colorants, sweeteners, and binders.

[0034] Examples of excipients include starches, celluloses, sugars, and sugar alcohols. Examples of starches include corn starch and maize starch. Examples of celluloses include crystalline cellulose and ethyl cellulose. Examples of sugars include lactose monohydrate and sucrose. Examples of sugar alcohols include D-sorbitol and D-mannitol. One excipient may be used, or two or more may be used in combination.

[0035] Examples of stabilizers include calcium chloride, calcium chloride hydrate, calcium chloride dihydrate, dibutylhydroxytoluene, alanine, and sodium chloride. One stabilizer may be used, or two or more may be used in combination.

[0036] Examples of lubricants include talc, magnesium stearate, calcium stearate, stearic acid, and light anhydrous silicic acid. One lubricant may be used, or two or more may be used in combination.

[0037] Examples of disintegrants include sodium starch glycolate, crospovidone, sodium bicarbonate, partially pregelatinized starch, low-substituted hydroxypropylcellulose, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, sodium crosscarboxymethylcellulose, and corn starch. One disintegrant may be used, or two or more may be used in combination.

[0038] Examples of coating agents include water-soluble polymers such as hypromellose and polyvinyl alcohol, as well as talc, titanium dioxide, and silicic acid. The coating agent may be used individually or in combination of two or more types.

[0039] Examples of coloring agents include ferric oxide, yellow ferric oxide, titanium dioxide, aluminum lake, and Yellow No. 5. One coloring agent may be used, or two or more may be used in combination.

[0040] Examples of pharmaceutically acceptable sweeteners include acesulfame potassium, sucralose, aspartame, and sodium saccharin. One sweetener may be used, or a combination of two or more may be used.

[0041] The pharmaceutical composition of this embodiment may optionally contain binders other than the cellulose derivatives and polyvinylpyrrolidone as pharmaceutically acceptable pharmaceutical additives. Examples of binders other than cellulose derivatives and polyvinylpyrrolidone include polyethylene glycol, lactose, agar, pectin, and amylopectin. The binders other than cellulose derivatives and polyvinylpyrrolidone may be one type or a combination of two or more types.

[0042] The content of the pharmaceutical additive contained in the pharmaceutical composition is, for example, 90% by mass or less, 85% by mass or less, 80% by mass or less, 75% by mass or less, 70% by mass or less, 65% by mass or less, 60% by mass or less, 55% by mass or less, 50% by mass or less, 45% by mass or less. 40% by mass or less, 35% by mass or less, 30% by mass or less, 25% by mass or less, 20% by mass or less, 15% by mass or less, 12.5% ​​by mass or less, 10% by mass or less, 7.5% by mass or less, 5% by mass or less, 4% by mass or less, or 3% by mass or less.

[0043] The water content in the pharmaceutical composition of this embodiment is not particularly limited and can be adjusted as appropriate, but it is preferably adjusted to 5% by mass or less, and more preferably to 3% by mass or less. The water content can be measured, for example, based on the Karl Fischer method.

[0044] When the pharmaceutical composition of this embodiment is in the form of particles, the average particle diameter (D) of the particles of the pharmaceutical composition is 50 The average particle size (D) here is preferably 80 μm or more and 400 μm or less, and more preferably 100 μm or more and 300 μm or less. 50 ) is the mass-average particle size (D) measured by classification using sieves with mesh sizes of 710 μm, 500 μm, 355 μm, 250 μm, 180 μm, 150 μm, 106 μm, and 75 μm, based on the sieving test method specified in JIS Z 8815. 50 For sieving tests, for example, Tsutsui Rikagakukikai Co., Ltd.'s "MICRO VIBRO SIFTER M-2" and Seishin Corporation's "Robot Shifter RPS-205" can be used.

[0045] The form (dosage form) of the pharmaceutical composition in this embodiment is not particularly limited, and examples include tablets, granules, capsules, granules, and dry syrups. Among these, tablets or granules are preferred.

[0046] The dry syrup formulation may contain other particles in addition to the particles containing the active ingredient. For example, it may contain a mixture of lactose monohydrate, light anhydrous silicic acid, aspartame, and strawberry micron.

[0047] Tablets and capsules may be packaged as needed by PTP packaging, bottle filling, aluminum packaging, etc. Examples of PTP packaging materials include resins such as polyvinyl chloride, polypropylene, polyvinylidene chloride, polychlorotrifluoroethylene, polyethylene, polystyrene, or polycarbonate, and metals such as aluminum. These materials may be used individually or in combination. Examples of combinations include laminating polyvinyl chloride and polyvinylidene chloride, or laminating polyvinyl chloride and polychlorotrifluoroethylene. The above resins can be molded into resin sheets using known methods, and the tablets can be placed in molded pockets and then sealed with aluminum foil.

[0048] The PTP packaging may be further packaged in an aluminum pillow. This aluminum pillow may further contain a desiccant or oxygen absorber. Examples of desiccants include calcium chloride, calcium oxide, magnesium oxide, silica gel, or zeolite. Examples of oxygen absorbers include iron-based oxygen absorbers such as iron powder, and organic oxygen absorbers such as ascorbic acid, isoascorbic acid, hydroquinone, or catechol. These desiccants and oxygen absorbers may be used individually, in combination of multiple types, or in combination with other oxygen absorbers. An example of a product combining a desiccant and an oxygen absorber is Mitsubishi Gas Chemical Company's "PharmaKeep®".

[0049] Tablets, dry syrups, and granules may be filled into glass bottles or plastic bottles as needed, or individually packaged in aluminum foil. Examples of plastic bottle materials include the resin used for PTP packaging mentioned above. The aluminum foil packaging may be further enclosed in an aluminum foil pillow. This aluminum foil pillow may also contain the desiccant or oxygen absorber mentioned above.

[0050] (Method for producing a pharmaceutical composition containing perampanel anhydrous) One embodiment of the present invention is a method for producing a pharmaceutical composition comprising perampanel anhydride and a pharmaceutically acceptable cellulose derivative and / or polyvinylpyrrolidone. The pharmaceutical composition can be obtained by mixing perampanel anhydride with at least one of a pharmaceutically acceptable cellulose derivative and / or polyvinylpyrrolidone, and optionally with a pharmaceutical additive. The same pharmaceutical additives as described above can be used. The mixing can be carried out by methods known in the art. When mixing is done manually, for example, bag mixing may be performed by placing the materials in a suitable bag and stirring. When mixing is done mechanically, a mixer known in the art may be used. The mixer may be either a rotary mixer or a stationary mixer. A rotary mixer is a machine that mixes powder contained in a container by rotating the container itself. A stationary mixer is a machine that mixes powder contained in a container by rotating stirring blades, screws, etc., provided inside the container. Examples of mixers include V-type mixers, double-cone mixers, ribbon mixers, and conical screw mixers. Alternatively, the mixture may be introduced into a device capable of granulation, such as a stirring granulator, for mixing.

[0051] The mixing of perampanel anhydrous, at least one of a pharmaceutically acceptable cellulose derivative and / or polyvinylpyrrolidone, and a pharmaceutical additive may be done in a single step or in multiple steps. For example, when mixing perampanel anhydrous with a cellulose derivative, the perampanel anhydrous and half of the cellulose derivative to be mixed may be mixed in a mortar, and the remaining half may be dissolved in purified water and then added to the sample after mixing in the mortar as a cellulose derivative solution. The amounts of perampanel anhydrous, cellulose derivative and / or polyvinylpyrrolidone, and pharmaceutical additive to be mixed can be appropriately set depending on the mixer used.

[0052] The manufactured pharmaceutical composition may be subjected to a granulation process to form granules, or to a tableting process to form tablets. Perampanel anhydrous may be crushed using an impact mill or the like before mixing. Crushing the perampanel anhydrous can further improve its dissolution properties. The impact mill is not particularly limited, and any device known in the art can be used. Examples of such devices include pin mills, hammer mills, disc mills, and ball mills.

[0053] (Method for manufacturing tablets containing perampanel anhydrous) One embodiment of the present invention is a method for producing tablets containing perampanel anhydrous. An example of this production method is described below.

[0054] First, perampanel anhydrous is mixed with at least one of a pharmaceutically acceptable cellulose derivative and polyvinylpyrrolidone, along with a pharmaceutical additive, to obtain a mixture. The mixing process is the same as described in the method for producing the pharmaceutical composition described above.

[0055] Next, the mixture and, if necessary, pharmaceutical additives are placed in a granulator and granulated to obtain granules containing perampanel anhydrous. The granulator is not particularly limited as long as it does not affect the physical properties of perampanel anhydrous. For example, a stirring granulator, a fluidized bed granulator, or a dry granulator can be used. The granules may also be dried in a granulator with a drying function or in a shelf dryer. The granulation mixture and granules may be classified by passing them through a sieve with a specific mesh size. By passing them through a sieve, the particle size of the granulation mixture and granules can be adjusted to an appropriate size.

[0056] The particle size of the granulation mixture or granules is not particularly limited, but the average particle size (D 50 The average particle size (D) here is preferably 100 μm or more and 400 μm or less, more preferably 100 μm or more and 200 μm or less, and more preferably 100 μm or more and 150 μm or less. 50) is the mass-average particle size (D) measured by classification using sieves with mesh sizes of 500 μm, 355 μm, 250 μm, 180 μm, 150 μm, 106 μm, and 75 μm, based on the sieving test method specified in JIS Z 8815. 50 )

[0057] The obtained granules are mixed with, if necessary, pharmaceutical additives and, if necessary, other granules or granules produced separately to obtain a tableting mixture. The mixing machine described above can be used to mix the granules and pharmaceutical additives. The amount of granules and pharmaceutical additives to be mixed can be appropriately set depending on the mixing machine used.

[0058] Other granules include, for example, rapidly disintegrating granules. Rapidly disintegrating granules can be obtained, for example, by mixing an excipient (e.g., D-mannitol or ethylcellulose) and a lubricant (e.g., light anhydrous silicic acid) in a fluidized bed granulator and dryer, then spraying a granulated solution containing a disintegrant (e.g., corn starch or crospovidone) and a coloring agent (e.g., yellow ferric oxide and ferric oxide) dispersed in purified water, and drying it. The above-mentioned excipients, lubricants, disintegrants, and coloring agents can be used as appropriate for pharmaceutical additives.

[0059] Tablets (plain tablets) can be obtained by compressing the resulting tablet mixture using a tablet press. "Plain tablets" refers to tablets that have not undergone coating treatment. Any known tablet press can be used for compression molding. For example, a rotary tablet press can be used.

[0060] The resulting tablets may be further coated as needed. Known coating methods can be used for coating. For example, pan coating or fluidized bed coating methods can be used. The coating agent used can be appropriately selected from those described above. The coating agent can be prepared as a film coating solution.

[0061] The mass of the tablets produced is not particularly limited, but it is preferable that the tablets contain at least 0.5 mg of the compound represented by formula (I). The mass of the tablets is, for example, 20 mg to 1000 mg per tablet, preferably 30 mg to 500 mg, and more preferably 40 mg to 300 mg.

[0062] The hardness of the manufactured tablets is not particularly limited, but is preferably between 30N and 120N, and more preferably between 50N and 100N. In this specification, hardness is a value measured using a hardness tester and applying a load to the tablet with an indenter using an electric weight loader.

[0063] The compression pressure used when manufacturing tablets is not particularly limited and can be set appropriately depending on the composition and weight of the tablets. For example, the compression pressure can be set to 4kN or more and 15kN or less, and preferably to 5kN or more and 13kN or less.

[0064] (Method for producing fine granules containing perampanel anhydrous) One embodiment of the present invention is a method for producing fine granules containing perampanel anhydrous. An example of this production method is described below.

[0065] First, perampanel anhydrous is mixed with at least one of a pharmaceutically acceptable cellulose derivative and polyvinylpyrrolidone, along with a pharmaceutical additive, to obtain a mixture. The pharmaceutical additive and the mixture are the same as those described in the method for producing the pharmaceutical composition above. This mixture may be classified, for example, by passing it through a sieve to obtain fine granules.

[0066] Next, the mixture and, if necessary, pharmaceutical additives are placed in a granulator and granulated to obtain granules containing perampanel anhydrous. The granulator is not particularly limited and, for example, the one described above can be used, but it is preferable to use a device that can reduce the particle size of the granules, such as a crushing granulator. These granules can be passed through a sieve to classify them and obtain fine particles.

[0067] The resulting granules may be further pulverized using an impact pulverizer or the like. The pulverized powder may be passed through a sieve to classify it and obtain fine granules.

[0068] The particle size of the fine particles produced is not particularly limited, but the average particle size (D 50 The average particle size (D) here is preferably 100 μm or more and 400 μm or less, and more preferably 200 μm or more and 300 μm or less. 50 ) is the mass-average particle size (D) measured by classification using sieves with mesh sizes of 710 μm, 500 μm, 355 μm, 250 μm, 180 μm, 150 μm, 106 μm, and 75 μm, based on the sieving test method specified in JIS Z 8815. 50 )

[0069] (Method for improving the elution properties of perampanel anhydrous) One embodiment of the present invention is a method for improving the dissolution properties of perampanel anhydrous. By mixing perampanel anhydrous with at least one of a pharmaceutically acceptable cellulose derivative and polyvinylpyrrolidone to produce a pharmaceutical composition, and then producing tablets using this pharmaceutical composition, the dissolution properties of perampanel anhydrous can be improved compared to tablets that do not use the cellulose derivative and polyvinylpyrrolidone. Details of the production of tablets in this method are the same as those described above for the production of tablets in this embodiment.

[0070] The present invention will be described in more detail below with reference to examples and comparative examples, but the present invention is not limited thereto. [Examples]

[0071] Tablets were manufactured by compounding perampanel with various pharmaceutical additives, and the dissolution properties of perampanel were investigated. The manufacturing process for each tablet is described below. The specific composition of each tablet is summarized in Tables 1-3 below. Unless otherwise specified, the units of the values ​​in Tables 1-3 are mg. In the following examples and comparative examples, the volume-average particle size (D) of perampanel anhydrous (unground) is 10 ) is 1.2 μm, volume average particle size (D 50 ) is 4.8 μm, volume average particle size (D 90 The volume average particle size (D) of Perampanel anhydrous (ground) is 12.9 μm. 10 ) is 0.9 μm, volume average particle size (D 50 ) is 3.6 μm, volume average particle size (D 90 The diameter is 11.9 μm. Furthermore, the molecular weight (GPC) of hydroxypropyl cellulose (HPC-SL) is approximately 100,000 and its viscosity is 3.0-5.9 mPa·s, while the molecular weight (GPC) of hydroxypropyl cellulose (HPC-SSL) is approximately 40,000 and its viscosity is 2.0-2.9 mPa·s. For polyvinylpyrrolidone (also called povidone), a molecular weight (GPC) of approximately 44,000-54,000 and a viscosity of approximately 7 mPa·s (the viscosity of povidone is for a 10% by mass aqueous solution) was used.

[0072] Preparation of tablets containing perampanel anhydrous according to Examples 1-3, 5 and 6 Tablets containing perampanel anhydrous and hydroxypropyl cellulose (HPC-SL) as a binder were obtained. The tablets were manufactured as follows.

[0073] (Granule manufacturing) Anhydrous perampanel (unground) was mixed with D-mannitol to obtain a double-dried product. The obtained double-dried product, a portion of HPC-SL, and corn starch were added to a mortar and mixed with a pestle to obtain a mortar mixture. The remaining HPC-SL was dissolved in purified water, the mortar mixture was added to this, and granulation was performed with a pestle. The mixture was then placed in a vacuum dryer for drying and sieving to obtain granules.

[0074] (Manufacturing of rapidly disintegrating granules) Corn starch and crospovidone were dispersed in purified water as excipients, and yellow ferric oxide and ferric oxide were dispersed as colorants to obtain a granulation solution. D-mannitol, ethylcellulose, and light anhydrous silicic acid were added to a fluidized bed granulator and mixed. After mixing, the granulation solution was sprayed and then dried to obtain a granulation powder. This granulation powder was sized using a dry granulation machine to obtain rapidly disintegrating granules.

[0075] (Method of manufacturing tablets) The granules produced in the above process, rapidly disintegrating granules, and light anhydrous silicic acid were mixed in a bag. After mixing, magnesium stearate was added, and the resulting tablet mixture was compressed using a single-stroke tablet press at a compression pressure of 8 kN to obtain the tablets (plain tablets) of Examples 1-3, 5, and 6.

[0076] Preparation of tablets containing perampanel anhydrous in Example 4 The tablets (plain tablets) of Example 4 were obtained in the same manner as in Examples 1-3, 5, and 6, except that perampanel anhydrous (ground) was used instead of perampanel anhydrous (unground).

[0077] Preparation of tablets containing perampanel anhydrous according to Examples 7-9 Except for using HPC-SSL instead of HPC-SL, tablets (plain tablets) for Examples 7-9 were obtained in the same manner as in Examples 1-3, 5, and 6.

[0078] Preparation of tablets containing perampanel anhydrous according to Examples 10 and 11 Tablets (plain tablets) for Examples 10 and 11 were obtained in the same manner as in Examples 1-3, 5, and 6, except that polyvinylpyrrolidone was used instead of HPC-SL.

[0079] Preparation of tablets containing perampanel anhydrous according to Example 12 The tablets (plain tablets) of Example 12 were obtained in the same manner as in Examples 10 and 11, except that perampanel anhydrous (ground) was used instead of perampanel anhydrous (unground).

[0080] Manufacturing of tablets containing perampanel anhydrous in Comparative Example 1 In the tablet manufacturing methods of Examples 1-3, 5, and 6, the tablets of Comparative Example 1 (plain tablets) were obtained in the same manner as in Examples 1-3, 5, and 6, except that HPC-SL was not used.

[0081] [Table 1]

[0082] [Table 2]

[0083] [Table 3]

[0084] [Study on the dissolution properties of tablets] Dissolution tests were performed on the tablets of Examples 1-12 and Comparative Example 1 according to the dissolution test method (Method 2) described in the 17th edition of the Japanese Pharmacopoeia, with the paddle rotation speed set to 50 rpm and water (900 mL) used as the test solution. The test solution was collected at 0, 5, 15, and 30 minutes from the start of the test, and the drug concentration was measured using a spectrophotometer.

[0085] The measurement results for dissolution are shown in Figures 1 to 3. Figure 1 shows the measurement results for tablets of Comparative Example 1 and Examples 1 to 6 (Note that Examples 5 and 6 in Figure 1 overlap in Figure 1 because the measurement results were almost the same). Figure 2 shows the measurement results for tablets of Comparative Example 1 and Examples 7 to 9. Figure 3 shows the measurement results for tablets of Comparative Example 1 and Examples 10 to 12. From Figures 1 to 3, it was shown that the tablets of Examples 1 to 12 showed improved dissolution of perampanel anhydrous compared to the tablet of Comparative Example 1 at all time points. Furthermore, it was also shown that the tablets of Examples 1 to 9 using HPL-SL and HPC-SSL, and the tablet of Example 12 using 8% by mass of polyvinylpyrrolidone, showed superior dissolution compared to the tablets of Examples 10 and 11.

[0086] From the above, it was shown that the dissolution of perampanel anhydrous is improved by manufacturing tablets using a pharmaceutical composition containing perampanel anhydrous and a pharmaceutically acceptable cellulose derivative and / or polyvinylpyrrolidone.

Claims

1. A pharmaceutical composition comprising perampanel anhydride and a pharmaceutically acceptable cellulose derivative and / or polyvinylpyrrolidone, The cellulose derivative is at least one selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, and carboxymethylcellulose. The elution properties of perampanel anhydride in the aforementioned pharmaceutical composition are higher than those of a pharmaceutical composition containing perampanel anhydride but not containing the cellulose derivative and the polyvinylpyrrolidone. The aforementioned pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the cellulose derivative is hydroxypropylcellulose.

3. The pharmaceutical composition according to claim 1 or 2, wherein the content of the cellulose derivative or polyvinylpyrrolidone is 0.1% by mass or more and 20% by mass or less of the total mass of the pharmaceutical composition.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the content of the perampanel anhydrous is 0.1% by mass or more and 20% by mass or less of the total mass of the pharmaceutical composition.

5. A pharmaceutical composition according to any one of claims 1 to 4, which is in the form of particles.

6. A pharmaceutical composition according to any one of claims 1 to 4, in the form of a tablet.

7. A method for producing a pharmaceutical composition containing perampanel anhydrous, comprising the step of mixing perampanel anhydrous with a pharmaceutically acceptable cellulose derivative and / or polyvinylpyrrolidone, The cellulose derivative is at least one selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, and carboxymethylcellulose. The elution properties of perampanel anhydride in the aforementioned pharmaceutical composition are higher than those of a pharmaceutical composition containing perampanel anhydride but not containing the cellulose derivative and the polyvinylpyrrolidone. The aforementioned manufacturing method.

8. A step of mixing perampanel anhydrous with a pharmaceutically acceptable cellulose derivative and / or polyvinylpyrrolidone to obtain a mixture, A step of granulating the mixture, The process of obtaining tablets by compressing and molding the aforementioned granules, A method for producing tablets containing perampanel anhydrous, The cellulose derivative is at least one selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, and carboxymethylcellulose. The dissolution rate of perampanel anhydrous in the aforementioned tablets is higher than that of tablets containing perampanel anhydrous but not containing the cellulose derivative and the polyvinylpyrrolidone. The aforementioned manufacturing method.

9. A pharmaceutical composition comprising perampanel anhydride and a pharmaceutically acceptable cellulose derivative and / or polyvinylpyrrolidone, The cellulose derivative is at least one selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, and carboxymethylcellulose. A method for improving the dissolution properties of perampanel anhydride compared to a pharmaceutical composition that contains perampanel anhydride but does not contain the cellulose derivative and the polyvinylpyrrolidone.

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