Pharmaceutical composition, method for producing the same, and method for stabilizing the pharmaceutical composition

Abstract

To provide a pharmaceutical composition containing mirogabalin or a salt thereof in which the generation of related substances is suppressed, a method for producing the same, and a method for stabilizing the pharmaceutical composition. [Solution] A pharmaceutical composition comprising mirogabalin or a salt thereof, wherein the pH of an aqueous solution or dispersion of the pharmaceutical composition obtained by adding 20 mL of purified water per 10 mg of mirogabalin or a salt thereof is 3.4 or less, or a pharmaceutical composition comprising mirogabalin or a salt thereof and an acidic additive or carboxymethylcellulose.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition, a method for producing the same, and a method for stabilizing the pharmaceutical composition.

Background Art

[0002] Mirogabalin is known as a ligand for the α2δ subunit of voltage-dependent calcium channels and has attracted attention as a therapeutic agent for neuropathic pain and the like. However, it is known that mirogabalin produces related substances over time and has poor stability (for example, Patent Document 1 and Patent Document 2, etc.).

[0003] Therefore, there is a strong demand for providing a pharmaceutical composition containing mirogabalin or a salt thereof in which the production of related substances is suppressed.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0005] An object of the present invention is to solve the above-described conventional problems and achieve the following objects. That is, an object of the present invention is to provide a pharmaceutical composition containing mirogabalin or a salt thereof in which the production of related substances is suppressed, a method for producing the same, and a method for stabilizing the pharmaceutical composition.

Means for Solving the Problems

[0006] As a result of diligent research conducted by the present inventors to achieve the above objective, they have found that it is possible to provide a pharmaceutical composition containing mirogabalin or a salt thereof in which the generation of related substances is suppressed, a method for producing the same, and a method for stabilizing the pharmaceutical composition.

[0007] The present invention is based on the aforementioned findings by the inventors, and the means for solving the aforementioned problems are as follows: <1> A pharmaceutical composition comprising mirogabalin or a salt thereof, The pharmaceutical composition is characterized in that the pH of an aqueous solution or dispersion of the pharmaceutical composition, obtained by adding 20 mL of purified water to 10 mg of the mirogabalin or its salt, is 3.4 or less. <2> Mirogabalin or its salt, This pharmaceutical composition is characterized by containing an acidic additive or carboxymethylcellulose. <3> Mirogabalin or its salt, This is a pharmaceutical composition characterized by containing amino acids. <4> Mirogabalin or its salt, This is a method for producing a pharmaceutical composition, characterized by including a step of mixing an acidic additive or carboxymethylcellulose. <5> Mirogabalin or its salt, This method for stabilizing a pharmaceutical composition is characterized by including a step of mixing an acidic additive or carboxymethylcellulose with the composition. [Effects of the Invention]

[0008] According to the present invention, it is possible to provide a pharmaceutical composition containing mirogabalin or a salt thereof in which the generation of related substances is suppressed, a method for producing the same, and a method for stabilizing the pharmaceutical composition. [Modes for carrying out the invention]

[0009] (Pharmaceutical composition) Examples of the means for solving the problems of the present invention include the first embodiment, the second embodiment, and the third embodiment.

[0010] <Pharmaceutical composition (first aspect)> The pharmaceutical composition (first embodiment) comprises mirogabalin or a salt thereof, and may further contain other components.

[0011] -Milogabalin or its salt- There are no particular restrictions on the salt of mirogabarin, and it can be appropriately selected depending on the purpose. For example, the salts of mirogabarin include: hydrohalides such as hydrofluoric acid, hydrochloride, hydrobromide, and hydroiodide; inorganic salts such as nitrates, sulfates, and phosphates; lower alkanesulfons such as methanesulfonates, trifluoromethanesulfons, and ethanesulfons; arylsulfons such as benzenesulfons and p-toluenesulfons; organic salts such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, and maleate; amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspartate. Examples include alkali metal salts such as thorium salts, potassium salts, and lithium salts; alkaline earth metal salts such as calcium salts and magnesium salts; metal salts such as aluminum salts and iron salts; inorganic salts such as ammonium salts; and amine salts such as t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, and tris(hydroxymethyl)aminomethane salt. Among these, inorganic salts or aryl sulfonates are preferred, hydrochlorides, benzenesulfonates, or p-toluenesulfonates are more preferred, and benzenesulfonates are even more preferred.

[0012] Specific examples of the salt of milogabaline include, for example, [(1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid benzenesulfonate (milogabaline besylate), and the like.

[0013] -Other components (first aspect)- The other components (first aspect) are not particularly limited and can be appropriately selected according to the purpose. For example, acidic additives or carboxymethyl cellulose, amino acids, excipients, binders, lubricants, disintegrants, surfactants, plasticizers, colorants, and the like can be mentioned.

[0014] --Acidic additive or carboxymethyl cellulose-- The acidic additive is not particularly limited and can be appropriately selected according to the purpose. However, a phosphoric acid compound or an organic acid is preferable in terms of efficiently suppressing the production of related substances.

[0015] The phosphoric acid compound is not particularly limited and can be appropriately selected according to the purpose. However, phosphoric acid or pyrophosphoric acid is preferable in terms of efficiently suppressing the production of related substances, and phosphoric acid is more preferable. The phosphoric acid compound may be used alone or in combination of two or more.

[0016] The organic acid is not particularly limited and can be appropriately selected according to the purpose. However, a dicarboxylic acid is preferable in terms of efficiently suppressing the production of related substances, tartaric acid, succinic acid, or fumaric acid is more preferable, and tartaric acid or fumaric acid is even more preferable. The organic acid may be used alone or in combination of two or more.

[0017] The carboxymethyl cellulose is a derivative of cellulose, in which a carboxymethyl group is bonded to a part of the hydroxy groups of the glucopyranose monomers constituting the cellulose skeleton. It is also called carmellose.

[0018] The degree of substitution of the carboxymethyl cellulose is not particularly limited and can be appropriately selected according to the purpose, but is preferably 10% or more and 30% or less.

[0019] The weight-average molecular weight of the carboxymethyl cellulose is not particularly limited and can be appropriately selected according to the purpose, but is preferably 10,000 or more and 500,000 or less, more preferably 10,000 or more and 200,000 or less, and even more preferably 20,000 or more and 150,000 or less. The weight-average molecular weight can be measured by gel permeation chromatography (GPC).

[0020] The viscosity of the carboxymethyl cellulose is not particularly limited and can be appropriately selected according to the purpose, but is preferably 1 mPa·s or more and 100 mPa·s or less, more preferably 1 mPa·s or more and 50 mPa·s or less, and even more preferably 1 mPa·s or more and 10 mPa·s or less. The viscosity is a value obtained by measuring the viscosity of a 1% by mass solution of the compound to be measured based on the rotational viscometer method described in the Japanese Pharmacopoeia.

[0021] Commercially available products can be used as the carboxymethyl cellulose. Examples of commercially available products of the carboxymethyl cellulose include NS-300 manufactured by Nichirin Chemical Industry Co., Ltd.

[0022] The lower limit of the content of the acidic additive or carboxymethyl cellulose in the pharmaceutical composition is not particularly limited and can be appropriately selected according to the purpose, but in terms of efficiently suppressing the formation of related substances, 0.01% by mass or more is preferable, 0.1% by mass or more is more preferable, 0.3% by mass or more is even more preferable, and 0.5% by mass or more is particularly preferable. There are no particular restrictions on the upper limit of the content of the acidic additive or carboxymethylcellulose in the pharmaceutical composition, and it can be appropriately selected depending on the purpose. However, in terms of efficiently suppressing the generation of related substances, it is preferable to have 15% by mass or less, more preferably 10% by mass or less, even more preferably 7.5% by mass or less, even more preferably 5% by mass or less, particularly preferably 3% by mass or less, and most preferably 2.5% by mass or less. Furthermore, it is preferable that the lower limit and upper limit of the numerical range be one of the numbers indicated as the lower limit and one of the numbers indicated as the upper limit. Among these, in terms of efficiently suppressing the generation of related substances, 0.01% by mass or more and 15% by mass or less is preferred, 0.1% by mass or more and 10% by mass or less is more preferred, 0.3% by mass or more and 7.5% by mass or less is even more preferred, 0.5% by mass or more and 5% by mass or less is even more preferred, 1% by mass or more and 3% by mass or less is particularly preferred, and 1.5% by mass or more and 2.5% by mass or less is most preferred.

[0023] --amino acid-- There are no particular restrictions on the aforementioned amino acid, and it can be appropriately selected depending on the purpose, but methionine is preferred in that it efficiently suppresses the production of related substances. The aforementioned amino acids may be used individually or in combination of two or more.

[0024] --Excipients-- The excipients are not particularly limited and can be appropriately selected depending on the purpose. Examples include D-mannitol, light anhydrous silicic acid, ethylcellulose, corn starch, partially pregelatinized starch, lactose (e.g., lactose monohydrate), sucrose, calcium phosphate, sorbitol, crystalline cellulose, and the like. Among these, D-mannitol, light anhydrous silicic acid, ethylcellulose, corn starch, or partially pregelatinized starch are preferred. The aforementioned excipients may be used individually or in combination of two or more.

[0025] --Binder-- The binder is not particularly limited and can be appropriately selected depending on the purpose. Examples include hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), polyvinylpyrrolidone (povidone), methylcellulose, hydroxyethyl cellulose, carboxymethylcellulose (carmellose), polyvinyl alcohol (partially saponified), polyvinyl alcohol (fully saponified), copolymers of N-vinylpyrrolidone and vinyl acetate, or combinations thereof, pregelatinized starch, gelatin, agar, and gum arabic. The aforementioned binder may be used alone or in combination of two or more types.

[0026] --lubricant-- There are no particular restrictions on the lubricant, and it can be appropriately selected depending on the purpose. Examples include inert substances such as talc, kaolin, and titanium dioxide, magnesium stearate, calcium stearate, stearic acid, light anhydrous silicic acid, finely ground silicon dioxide, sodium stearyl fumarate, glycerin fatty acid esters, and magnesium aluminometasilicate. Among these, magnesium stearate is preferred. The aforementioned lubricant may be used alone or in combination of two or more types.

[0027] --Disintegrant-- The disintegrant is not particularly limited and can be appropriately selected depending on the purpose. Examples include partially pregelatinized starch, crospovidone, low-substituted hydroxypropyl cellulose, sodium starch glycolate, croscarmellose sodium, carboxymethylcellulose (carmellose), carmellose calcium, and potato starch. Among these, partially pregelatinized starch is preferred. The aforementioned disintegrant may be used alone or in combination of two or more types.

[0028] -pH (First aspect)- In the pharmaceutical composition containing mirogabalin or a salt thereof, the upper limit of the pH of the aqueous solution or dispersion of the pharmaceutical composition obtained by adding 20 mL of purified water per 10 mg of mirogabalin or a salt thereof is not particularly limited as long as it is 3.4 or less, and can be appropriately selected depending on the purpose. However, in terms of efficiently suppressing the generation of related substances, a pH of 3.2 or less is preferred, 3.0 or less is more preferred, and 2.9 or less is even more preferred. In the pharmaceutical composition containing mirogabalin or a salt thereof, there are no particular restrictions on the lower limit of the pH of the aqueous solution or dispersion of the pharmaceutical composition obtained by adding 20 mL of purified water per 10 mg of mirogabalin or a salt thereof, and it can be appropriately selected depending on the purpose, but 1.2 or higher is preferred.

[0029] The pH is determined by dissolving or dispersing the pharmaceutical composition containing mirogabalin or its salt in purified water so that the mirogabalin or its salt is present at 500 μg / mL, and then measuring the pH of the solution filtered through a 0.45 μm filter.

[0030] <Pharmaceutical composition (second aspect)> The pharmaceutical composition (second embodiment) comprises mirogabalin or a salt thereof, an acidic additive or carboxymethylcellulose, and may further contain other components. The mirogabalin or salt thereof is as described in "-Mirogabalin or salt thereof-" of the above-mentioned <Pharmaceutical Composition (First Embodiment)>. The acidic additive or carboxymethylcellulose is as described in "--acidic additive or carboxymethylcellulose--" of the above-mentioned <Pharmaceutical Composition (First Embodiment)>.

[0031] -Other components (second aspect)- The aforementioned other components (second embodiment) are not particularly limited and can be appropriately selected depending on the purpose. Examples include amino acids, excipients, binders, lubricants, disintegrants, surfactants, plasticizers, and colorants. The aforementioned amino acids are as described in "--Amino Acid--" of the above-mentioned <Pharmaceutical Composition (First Embodiment)>. The excipient is as described in "--Excipient--" of the above-mentioned <Pharmaceutical Composition (First Embodiment)>. The binder is as described in "--Binder--" of the above-mentioned <Pharmaceutical Composition (First Embodiment)>. The lubricant is as described in "--Lubricant--" of the above-mentioned <Pharmaceutical Composition (First Embodiment)>. The disintegrant is as described in "--Disintegrant--" of the above-mentioned <Pharmaceutical Composition (First Embodiment)>.

[0032] -pH (Second aspect)- In the pharmaceutical composition containing mirogabalin or a salt thereof, there are no particular restrictions on the upper limit of the pH of the aqueous solution or dispersion of the pharmaceutical composition obtained by adding 20 mL of purified water per 10 mg of mirogabalin or a salt thereof, and it can be appropriately selected depending on the purpose. However, in terms of efficiently suppressing the generation of related substances, a pH of 3.4 or less is preferred, 3.2 or less is more preferred, 3.0 or less is even more preferred, and 2.9 or less is particularly preferred. In the pharmaceutical composition containing mirogabalin or a salt thereof, there are no particular restrictions on the lower limit of the pH of the aqueous solution or dispersion of the pharmaceutical composition obtained by adding 20 mL of purified water per 10 mg of mirogabalin or a salt thereof, and it can be appropriately selected depending on the purpose, but 1.2 or higher is preferred. The pH is determined by dissolving or dispersing the pharmaceutical composition containing mirogabalin or its salt in purified water so that the mirogabalin or its salt is present at 500 μg / mL, and then measuring the pH of the solution filtered through a 0.45 μm filter.

[0033] <Pharmaceutical composition (third aspect)> The pharmaceutical composition (third embodiment) comprises mirogabalin or a salt thereof, an amino acid, and may further contain other components. The mirogabalin or salt thereof is as described in "-Mirogabalin or salt thereof-" of the above-mentioned <Pharmaceutical Composition (First Embodiment)>. The aforementioned amino acids are as described in "--Amino Acid--" of the above-mentioned <Pharmaceutical Composition (First Embodiment)>.

[0034] -Other components (second aspect)- The aforementioned other components (second embodiment) are not particularly limited and can be appropriately selected depending on the purpose. Examples include acidic additives or carboxymethylcellulose, amino acids, excipients, binders, lubricants, disintegrants, surfactants, plasticizers, and colorants. The acidic additive or carboxymethylcellulose is as described in "--acidic additive or carboxymethylcellulose--" of the above-mentioned <Pharmaceutical Composition (First Embodiment)>. The excipient is as described in "--Excipient--" of the above-mentioned <Pharmaceutical Composition (First Embodiment)>. The binder is as described in "--Binder--" of the above-mentioned <Pharmaceutical Composition (First Embodiment)>. The lubricant is as described in "--Lubricant--" of the above-mentioned <Pharmaceutical Composition (First Embodiment)>. The disintegrant is as described in "--Disintegrant--" of the above-mentioned <Pharmaceutical Composition (First Embodiment)>.

[0035] -pH (Third aspect)- In the pharmaceutical composition containing mirogabalin or a salt thereof, there are no particular restrictions on the upper limit of the pH of the aqueous solution or dispersion of the pharmaceutical composition obtained by adding 20 mL of purified water per 10 mg of mirogabalin or a salt thereof, and it can be appropriately selected depending on the purpose. However, in terms of efficiently suppressing the generation of related substances, a pH of 3.4 or less is preferred, 3.2 or less is more preferred, 3.0 or less is even more preferred, and 2.9 or less is particularly preferred. In the pharmaceutical composition containing mirogabalin or a salt thereof, there are no particular restrictions on the lower limit of the pH of the aqueous solution or dispersion of the pharmaceutical composition obtained by adding 20 mL of purified water per 10 mg of mirogabalin or a salt thereof, and it can be appropriately selected depending on the purpose, but 1.2 or higher is preferred. The pH is determined by dissolving or dispersing the pharmaceutical composition containing mirogabalin or its salt in purified water so that the mirogabalin or its salt is present at 500 μg / mL, and then measuring the pH of the solution filtered through a 0.45 μm filter.

[0036] (Method of manufacturing pharmaceutical compositions) The method for producing the pharmaceutical composition may include a mixing step and may further include other steps.

[0037] -Mixing process- The aforementioned mixing step is a step of mixing mirogabalin or a salt thereof with an acidic additive or carboxymethylcellulose. In the aforementioned mixing step, other components may be added. The mirogabalin or salt thereof is as described in "-Mirogabalin or salt thereof-" of the above-mentioned <Pharmaceutical Composition (First Embodiment)>. The acidic additive or carboxymethylcellulose is as described in "--acidic additive or carboxymethylcellulose--" of the above-mentioned <Pharmaceutical Composition (First Embodiment)>. The aforementioned other components are as described in the section "Other Components (Second Embodiment)" of the above-mentioned <Pharmaceutical Composition (Second Embodiment)>.

[0038] There are no particular restrictions on the aforementioned mixture, and it can be appropriately selected according to the purpose.

[0039] -Other processes- The aforementioned other processes are not particularly limited and can be appropriately selected depending on the purpose, for example, a tableting process.

[0040] There are no particular restrictions on the compression pressure in the tableting process, and it can be appropriately selected depending on the purpose, but it is preferably 0.5kN or more and 20kN or less, more preferably 1kN or more and 15kN or less, and even more preferably 5kN or more and 9kN or less.

[0041] As an example of manufacturing conditions for obtaining the above-mentioned pharmaceutical composition as tablets, the conditions include using mirogabalin type I crystals (Form I) as the crystalline polymorphism of the active pharmaceutical ingredient, having a tablet hardness of 40kN or more and 60kN or less, and having an active pharmaceutical ingredient particle size D50 of 16μm. The mirogabalin type I crystal (Form I) described above is the one described in International Publication No. 2018 / 003980.

[0042] (Method for stabilizing pharmaceutical compositions) The method for stabilizing the pharmaceutical composition includes a mixing step and may further include other steps. The mixing step is as described in the "-Mixing Step-" section of the above-mentioned (Method for Producing a Pharmaceutical Composition) The aforementioned other steps are as described in "-Other Steps-" of the above-mentioned (Method for Manufacturing Pharmaceutical Compositions) [Examples]

[0043] The following describes embodiments of the present invention, but the present invention is not limited in any way to these embodiments.

[0044] <Manufacturing of Pharmaceutical Compositions 1> The tablets were manufactured using a direct compression method, in which the additives were granulated, the active ingredients were mixed with them, and then compressed and molded.

[0045] (Manufacturing Example 1: Manufacturing of Rapidly Decaying Particles 1) D-mannitol, ethylcellulose, and light anhydrous silicic acid were weighed out in the amounts shown in Table 1 and fed into a fluidized bed granulator. A dispersion of corn starch and partially pregelatinized starch in purified water, also in the amounts shown in Table 1, was sprayed onto the granulator. After drying, the granulator was sized to obtain rapidly disintegrating particles.

[0046] [Table 1]

[0047] (Example 1) -mixture- The rapidly disintegrating particles, mirogabalin besylate, and light anhydrous silicic acid produced in Production Example 1 were weighed out in the amounts shown in Table 2 and mixed for 1 minute. Then, magnesium stearate (plant-derived (Taihei Chemical Industry Co., Ltd.)) was weighed out in the amounts shown in Table 2 and added to the mixed powder, and mixed for 30 seconds.

[0048] -Tableting- Using a tablet press (VELA, manufactured by Kikusui Seisakusho Co., Ltd.), the tablets were formed with a mass of 112 mg and a compression pressure of 7 kN to obtain round tablets (diameter 6.5 mm).

[0049] [Table 2]

[0050] (Test example 1, Test examples 3 to 5, Test examples 7 to 9) -mixture- The ingredients other than magnesium stearate, as shown in Table 2, were weighed out in the quantities shown in Table 2 and mixed for 1 minute. Then, magnesium stearate, as shown in the quantities shown in Table 2, was weighed out and added to the mixture, and mixed for 30 seconds.

[0051] -Tableting- Using a tablet press (Hand Tab, manufactured by Ichihashi Seiki Kogyo Co., Ltd.), the tablets were formed with a mass of 112 mg and a compression pressure of 7 kN to obtain round tablets (diameter 6.5 mm).

[0052] (Test example 2, Test example 6) -mixture- Phosphoric acid and light anhydrous silicic acid were weighed out in the amounts shown in Table 3. The phosphoric acid was mixed with the light anhydrous silicic acid, and the mixture was passed through a sieve with a mesh size of 500 μm to obtain the double-spread sieved product. Next, the components other than magnesium stearate, as shown in Table 4, were weighed out in the amounts shown in Table 4 and mixed for 1 minute. Then, magnesium stearate, as shown in Table 4, was weighed out and added to the mixture, and mixed for 30 seconds.

[0053] -Tableting- A round tablet was obtained in the same manner as in Test Example 1 (diameter 6.5 mm).

[0054] [Table 3]

[0055] [Table 4]

[0056] <Evaluation Method> -Analysis of related substances- For tablets manufactured according to Reference Example 1 and Test Examples 1 to 9, the related substances of mirogabalin besylate (decomposition product A and all related substances) were measured by high-performance liquid chromatography under the analytical conditions shown in Table 5, before storage (Initial), after storage for 2 or 4 weeks under open conditions at 40°C and 75% RH (relative humidity), and after storage for 9 days at 70°C in a resealable aluminum pillow bag. The aforementioned degradation product A is a related substance that, when measured under the analytical conditions shown in Table 5, exhibits a peak at a relative retention time (RRT) of 1.3. The total related substances are all related substances other than the active ingredient (mirogabalin besylate). The results are shown in Table 6. In Table 6, "nd" indicates that the detection limit was not met.

[0057] -pH measurement- For the tablets manufactured according to Reference Example 1 and Test Examples 1 to 9, the tablets were dissolved or dispersed in purified water to a concentration of 500 μg / mL of the active ingredient (mirogabalin besylate), and the pH of the solution filtered through a 0.45 μm filter was measured. The results are shown in Table 6.

[0058] [Table 5]

[0059] [Table 6]

[0060] <Manufacturing of Pharmaceutical Compositions 2> The additives and active pharmaceutical ingredients were mixed, and a compatibility test was conducted as described below.

[0061] -Preparation of Test Examples 10-16- Mirogabalin besylate and the components (various additives) listed in Table 7 were weighed out in a mass ratio of 1:5 and mixed in a glass screw vial to prepare the sample.

[0062] -Preparation of Test Example 17- Mirogabalin besylate and corn starch were weighed out in a glass screw vial in a mass ratio of 1:25 and mixed to prepare the sample.

[0063] <Evaluation Method> For the samples prepared in Test Examples 10 to 17, related substances (decomposition product A and all related substances) were measured by high-performance liquid chromatography under the analytical conditions shown in Table 5, before standing (Initial), after standing for 4 weeks under open and sealed conditions at 40°C and 75% RH (relative humidity), and after standing for 21 days at 60°C in a resealable aluminum pillow. The aforementioned degradation product A is a related substance that, when measured under the analytical conditions shown in Table 5, exhibits a peak at a relative retention time (RRT) of 1.3. The total related substances are all related substances other than the active ingredient (mirogabalin besylate). The results are shown in Table 7. In Table 7, "nd" indicates that the detection limit was not met.

[0064] [Table 7]

[0065] <Manufacturing of Pharmaceutical Compositions 3> The tablets were manufactured using a direct compression method, in which the additives were granulated, the active ingredients were mixed with them, and then compressed and molded.

[0066] (Manufacturing Example 2: Manufacturing of Rapidly Decaying Particles 2) (Manufacturing Example 2-1) D-mannitol, ethylcellulose, and light anhydrous silicic acid were weighed out in the amounts shown in Table 8 and fed into a fluidized bed granulator. A dispersion of corn starch and crospovidone in purified water, also in the amounts shown in Table 8, was sprayed onto the granulator, and after drying, the particles were sized to obtain rapidly disintegrating particles.

[0067] (Manufacturing Example 2-2) D-mannitol, ethylcellulose, and light anhydrous silicic acid were weighed out in the amounts shown in Table 8 and fed into a fluidized bed granulator. A dispersion of corn starch and partially pregelatinized starch in purified water, also in the amounts shown in Table 8, was sprayed onto the granulator. After drying, the granulator was sized to obtain rapidly disintegrating particles.

[0068] (Manufacturing Example 2-3) D-mannitol, ethylcellulose, light anhydrous silicic acid, and sodium starch glycolate were weighed out in the quantities shown in Table 8 and fed into a fluid bed granulator. A dispersion of corn starch dispersed in purified water in the quantities shown in Table 8 was sprayed onto the mixture, and after drying, the mixture was granulated to obtain rapidly disintegrating particles.

[0069] (Manufacturing Example 2-4) D-mannitol, ethylcellulose, light anhydrous silicic acid, and low-substituted hydroxypropylcellulose were weighed out in the amounts shown in Table 8 and fed into a fluidized bed granulator. A dispersion of partially pregelatinized starch dispersed in purified water in the amounts shown in Table 8 was sprayed onto the granulator, and after drying, the particles were sized to obtain rapidly disintegrating particles.

[0070] (Manufacturing Example 2-5) D-mannitol, ethylcellulose, light anhydrous silicic acid, and carboxymethylcellulose were weighed out in the amounts shown in Table 8 and fed into a fluidized bed granulator. A dispersion of partially pregelatinized starch dispersed in purified water in the amounts shown in Table 8 was sprayed onto the granulator, and after drying, the particles were sized to obtain rapidly disintegrating particles.

[0071] (Manufacturing Example 2-6) D-mannitol, ethylcellulose, light anhydrous silicic acid, carboxymethylcellulose, and low-substituted hydroxypropylcellulose were weighed out in the amounts shown in Table 8 and fed into a fluidized bed granulator. Purified water in the amounts shown in Table 8 was sprayed over the mixture, and after drying, the particles were sized to obtain rapidly disintegrating particles.

[0072] (Manufacturing Example 2-7) D-mannitol, ethylcellulose, light anhydrous silicic acid, and carboxymethylcellulose were weighed out in the quantities shown in Table 8 and fed into a fluidized bed granulator. A dispersion of crospovidone dispersed in purified water in the quantities shown in Table 8 was sprayed onto the granulator, and after drying, the particles were sized to obtain rapidly disintegrating particles.

[0073] [Table 8]

[0074] (Test examples 18 to 24) -mixture- The rapidly disintegrating particles obtained in any of Production Examples 2-1 to 2-7, along with mirogabalin besylate and light anhydrous silicic acid, were weighed out in the amounts shown in Table 9 and mixed for 1 minute. Then, magnesium stearate was weighed out in the amount shown in Table 9 and added to the mixture, and mixed for 30 seconds.

[0075] -Tableting- Using a tablet press (VELA, manufactured by Kikusui Seisakusho Co., Ltd.), the tablets were formed with a mass of 112 mg and a compression pressure of 7 kN to obtain round, uncoated tablets (diameter 6.5 mm).

[0076] [Table 9]

[0077] <Evaluation Method> -Analysis of related substances- For the tablets manufactured in Test Examples 18 to 24, related substances (decomposition product A and total related substances) were measured by high-performance liquid chromatography under the analytical conditions shown in Table 5, both before storage (Initial) and after being stored for two weeks under open conditions at 40°C and 75% RH (relative humidity). The aforementioned degradation product A is a related substance that, when measured under the analytical conditions shown in Table 5, exhibits a peak at a relative retention time (RRT) of 1.3. The total related substances are all related substances other than the active ingredient (mirogabalin besylate). The results are shown in Table 10. In Table 10, "nd" indicates that the detection limit was not met.

[0078] [Table 10]

[0079] From the above results, it was found that in a pharmaceutical composition containing mirogabalin or a salt thereof, the pH of the aqueous solution or dispersion of the pharmaceutical composition obtained by adding 20 mL of purified water per 10 mg of mirogabalin or a salt thereof is 3.4 or less, or in a pharmaceutical composition containing mirogabalin or a salt thereof and an acidic additive or carboxymethylcellulose, the formation of related substances of mirogabalin or a salt thereof is suppressed.

[0080] Examples of embodiments of the present invention include the following: <1> A pharmaceutical composition comprising mirogabalin or a salt thereof, The pharmaceutical composition is characterized in that the pH of an aqueous solution or dispersion of the pharmaceutical composition, obtained by adding 20 mL of purified water to 10 mg of the mirogabalin or its salt, is 3.4 or less. <2> The pH of the aqueous solution or dispersion of the pharmaceutical composition obtained by adding 20 mL of purified water to 10 mg of mirogabalin or its salt is 3.0 or less. <1> This is the pharmaceutical composition described in [the relevant document]. <3> The above, containing an acidic additive or carboxymethylcellulose. <1> This is the pharmaceutical composition described in [the relevant document]. <4> Mirogabalin or its salt, This pharmaceutical composition is characterized by containing an acidic additive or carboxymethylcellulose. <5> The acidic additive includes a phosphoric acid compound or an organic acid. <3> or <4> This is the pharmaceutical composition described in [the relevant document]. <6> The phosphate compound is phosphoric acid or pyrophosphate, The organic acid is a dicarboxylic acid. <5> This is the pharmaceutical composition described in [the relevant document]. <7> The dicarboxylic acid is tartaric acid, succinic acid, or fumaric acid. <6> This is the pharmaceutical composition described in [the relevant document]. <8> The content of the acidic additive or carboxymethylcellulose in the pharmaceutical composition is 0.01% by mass or more and 15% by mass or less. <3> or <4> This is the pharmaceutical composition described in [the relevant document]. <9> Mirogabalin or its salt, This is a pharmaceutical composition characterized by containing amino acids. <10> The pH of the aqueous solution or dispersion of the pharmaceutical composition obtained by adding 20 mL of purified water to 10 mg of mirogabalin or its salt is 3.4 or less. <9> This is the pharmaceutical composition described in [the relevant document]. <11> The amino acid is methionine, <9> This is the pharmaceutical composition described in [the relevant document]. <12> Mirogabalin or its salt, This is a method for producing a pharmaceutical composition, characterized by including a step of mixing an acidic additive or carboxymethylcellulose. <13> Mirogabalin or its salt, This method for stabilizing a pharmaceutical composition is characterized by including a step of mixing an acidic additive or carboxymethylcellulose with the composition.

Claims

1. A pharmaceutical composition comprising mirogabalin or a salt thereof, A pharmaceutical composition characterized in that the pH of an aqueous solution or dispersion of the pharmaceutical composition, obtained by adding 20 mL of purified water to 10 mg of the mirogabalin or a salt thereof, is 3.4 or less.

2. The pharmaceutical composition according to claim 1, wherein the pH of an aqueous solution or dispersion of the pharmaceutical composition obtained by adding 20 mL of purified water to 10 mg of mirogabalin or a salt thereof is 3.0 or less.

3. The pharmaceutical composition according to claim 1, comprising an acidic additive or carboxymethylcellulose.

4. Mirogabalin or its salt, A pharmaceutical composition characterized by containing an acidic additive or carboxymethylcellulose.

5. The pharmaceutical composition according to claim 3 or 4, wherein the acidic additive comprises a phosphoric acid compound or an organic acid.

6. The phosphate compound is phosphoric acid or pyrophosphate, The pharmaceutical composition according to claim 5, wherein the organic acid is a dicarboxylic acid.

7. The pharmaceutical composition according to claim 6, wherein the dicarboxylic acid is tartaric acid, succinic acid, or fumaric acid.

8. The pharmaceutical composition according to claim 3 or 4, wherein the content of the acidic additive or carboxymethylcellulose in the pharmaceutical composition is 0.01% by mass or more and 15% by mass or less.

9. Mirogabalin or its salt, A pharmaceutical composition characterized by containing an amino acid.

10. The pharmaceutical composition according to claim 9, wherein the pH of an aqueous solution or dispersion of the pharmaceutical composition obtained by adding 20 mL of purified water to 10 mg of mirogabalin or a salt thereof is 3.4 or less.

11. The pharmaceutical composition according to claim 9, wherein the amino acid is methionine.

12. Mirogabalin or its salt, A method for producing a pharmaceutical composition, characterized by comprising the step of mixing an acidic additive or carboxymethylcellulose.

13. Mirogabalin or its salt, A method for stabilizing a pharmaceutical composition, characterized by comprising the step of mixing an acidic additive or carboxymethylcellulose with the composition.

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