Pharmaceutical composition containing mirogabalin

Abstract

The present invention addresses the problem of providing a solid preparation that contains a high-quality mirogabalin besylate and has excellent storage stability.　The solution of the present invention is a pharmaceutical solid preparation that contains mirogabalin besylate and does not substantially contain a reducing sugar.

Description

Pharmaceutical compositions containing mirogabalin The present invention provides a method for the preparation of a pharmaceutical solid formulation comprising the steps of: reducing the amount of reducing sugar contained in an additive used in the pharmaceutical solid formulation; and The present invention relates to improving the stability of [(1R,5S,6S)-6-(Aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid monobenzenesulfonate, hereinafter sometimes referred to as "mirogabalin besylate." Mirogabalin besylate is thought to exert its analgesic effect by inhibiting calcium currents through binding to the α2δ subunit, which plays an auxiliary role in the function of voltage-dependent calcium channels in the nervous system. Mirogabalin besylate has received manufacturing and marketing approval as a neuropathic pain treatment based on clinical trials conducted both domestically and overseas, and is currently on the market. Mirogabalin besylate is disclosed in the following patent documents: International Publication No. 2009 / 041453 International Publication No. 2014 / 163132 International Publication No. 2016 / 148263 International Publication No. 2016 / 148264 International Publication No. 2020 / 027019 International Publication No. 2021 / 132072 International Publication No. 2022 / 024979 The inventors have discovered that by reducing the reducing sugar contained in additives used in pharmaceutical solid formulations containing mirogabalin besylate as an active ingredient, the stability of the active ingredient, mirogabalin besylate, is dramatically improved, and the inventors have solved the problem by using high-purity additives, thereby completing the present invention. In other words, as described below, the present invention relates to a solid formulation and a method for producing the same in which the stability of mirogabalin besylate is ensured by using an additive with a low content of reducing sugar in the formulation of mirogabalin besylate. Preferred embodiments of the present invention are as follows. [1] Contains mirogabalin or a pharma- ceutically acceptable salt thereof; Containing one or more pharma- ceutically acceptable additives, at least The one or more pharma- ceutically acceptable additives include: Contains excipients and / or disintegrants, A pharmaceutical solid formulation that is substantially free of reducing sugars. [2] Contains mirogabalin or a pharma- ceutically acceptable salt thereof, Containing one or more pharma- ceutically acceptable additives, at least The one or more pharma- ceutically acceptable additives include: Contains excipients and / or disintegrants, A pharmaceutical solid preparation, in which the ratio of reducing sugar contained in the pharmaceutical solid preparation to mirogabalin or a pharma- ceutical acceptable salt thereof is 0.9 mol % or less. [3] A solid formulation according to [2], wherein the ratio of reducing sugar contained in one solid formulation to mirogabalin or a pharma- ceutically acceptable salt thereof is 0.7 mol % or less. [4] Contains mirogabalin or a pharma- ceutically acceptable salt thereof, Containing one or more pharma- ceutically acceptable additives, at least The one or more pharma- ceutically acceptable additives include: Contains excipients and / or disintegrants, A pharmaceutical solid preparation in which the ratio of related substances contained in one solid preparation to mirogabalin or a pharma- ceutical acceptable salt thereof is less than 0.24%. [5] A solid formulation described in [4], in which the ratio of related substances contained in one solid formulation to mirogabalin or a pharma- ceutically acceptable salt thereof is less than 0.20%. [6] A solid formulation described in [4], in which the ratio of related substances contained in one solid formulation to mirogabalin or a pharma- ceutically acceptable salt thereof is less than 0.18%. [7] The solid formulation according to any one of [4] to [6], wherein the related substances are measured after the solid formulation is subjected to an accelerated test under conditions of 40°C and 75% RH for 6 months. [8] 1. A solid formulation according to any one of [1] to [3], wherein the reducing sugar is one or more selected from the group consisting of glucose, fructose, galactose, maltose, lactose, lactulose, cellobiose, glyceraldehyde, arabinose, mannose, xylose, melibiose, maltotriose, and hydrates thereof. [9] A solid formulation comprising mannitol as an excipient, the solid formulation being any one of [1] to [8].

[0010] A solid formulation comprising carmellose or carmellose calcium as a disintegrant, which is any one of [1] to [9].

[0011] A solid formulation which is any one of [1] to

[0010] , wherein the solid formulation is a tablet.

[0012] A solid formulation in which mirogabalin or a pharma- ceutically acceptable salt thereof is mirogabalin besylate [1] to

[0011] .

[0013] A method for producing a solid formulation according to [2], wherein the ratio of reducing sugar to mirogabalin or a pharma- ceutically acceptable salt thereof in one solid formulation is 0.9 mol % or less.

[0014] A method for producing a pharmaceutical solid formulation according to [3], wherein the ratio of reducing sugar to mirogabalin or a pharma- ceutical acceptable salt thereof in one solid formulation is 0.7 mol % or less.

[0015] A method for producing a solid formulation according to

[0013] or

[0014] , wherein the reducing sugar is any one selected from the group consisting of glucose, fructose, galactose, maltose, lactose, lactulose, cellobiose, glyceraldehyde, arabinose, mannose, xylose, melibiose, maltotriose, and hydrates thereof.

[0016] A method for producing a solid formulation according to any one of

[0013] to

[0015] , wherein the excipient is mannitol.

[0017] A method for producing a solid formulation as defined in any one of

[0013] to

[0016] , wherein the disintegrant is carmellose or carmellose calcium.

[0018] A method for producing a solid formulation, wherein the solid formulation is a tablet, as described in any one of

[0013] to

[0017] .

[0019] A method for producing a solid formulation, wherein the mirogabalin or a pharma- ceutically acceptable salt thereof is mirogabalin besylate, as defined in any one of

[0013] to

[0018] . In the present invention, the stability of the active ingredient, mirogabalin besylate, can be dramatically improved by controlling the amount of reducing sugar in a pharmaceutical solid preparation. Specifically, the present invention was completed by measuring the content and using only excipients that meet certain standards, thereby successfully ensuring the stability of mirogabalin besylate. According to the present invention, it is possible to provide a solid preparation (particularly, a tablet) containing high-quality mirogabalin besylate. (Components and suitable contents) Mirogabalin besylate is known to be used as an active ingredient in the treatment of neuropathic pain, and information about it can be easily obtained from the Pharmaceuticals and Medical Devices Agency's website (https: / / www.pmda.go.jp / PmdaSearch / iyakuSearch). The content of mirogabalin besylate in the tablet used in the present invention, calculated as the free form based on the total weight of the uncoated tablet, is preferably 0.5-40% by weight, more preferably 0.5-25% by weight, and particularly preferably 0.5-10% by weight (and even more particularly preferably 1.0-5.0% by weight). Film-coated tablets containing mirogabalin besylate as the active ingredient are known to contain the following excipients, according to the Pharmaceuticals and Medical Devices Agency website (https: / / www.pmda.go.jp / PmdaSearch / iyakuSearch): mannitol, crystalline cellulose, carmellose calcium, tocopherol, citric acid hydrate, magnesium aluminometasilicate, magnesium stearate, hypromellose, titanium oxide, talc, yellow ferric oxide, and ferric oxide. In addition, for orally disintegrating tablets (OD tablets, Orally Disintegrating Tablets) containing mirogabalin besilate as the active ingredient, (https: / / www.pmda.go.jp / PmdaSearch / iyakuSearch) is known to contain the following excipients: mannitol, crystalline cellulose, carmellose, hydroxypropyl cellulose, tocopherol, citric acid hydrate, magnesium aluminometasilicate, pregelatinized starch, crospovidone, acesulfame potassium, yellow ferric oxide, and magnesium stearate. The package insert for the mirogabalin besylate preparation states the following about its dosage and instructions: "Usually, for adults, the initial dose of mirogabalin is 5 mg taken orally twice daily, followed by gradually increasing the dose by 5 mg at intervals of at least one week until a dose of 15 mg is taken orally twice daily. The dose can be increased or decreased as appropriate within the range of 10 mg to 15 mg depending on age and symptoms." The term "pharmaceutical acceptable salt" refers to a salt that can be used as a medicine. Mirogabalin has an amino group and a carboxy group in its structure, and can form a salt by reacting with a corresponding acid or base, so the term refers to the salt. Examples of salts based on an amino group include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide; inorganic acid salts such as hydrochloride, nitrate, perchlorate, sulfate, and phosphate; lower alkanesulfonates such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate; arylsulfonates such as benzenesulfonate and p-toluenesulfonate; organic acid salts such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, and maleate; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspartate. Among these, inorganic acid salts or arylsulfonates are preferred, and hydrochloride, benzenesulfonate, or p-toluenesulfonate are more preferred, with benzenesulfonate (sometimes referred to as besylate) being particularly preferred. Salts based on a carboxy group include alkali metal salts such as sodium 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; amine salts such as t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, chloroprocaine salts, procaine salts, diethanolamine salts, N-benzylphenethylamine salts, piperazine salts, tetramethylammonium salts, and tris(hydroxymethyl)aminomethane salts; and amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamate salts, and aspartate salts. "Additives" are important components that form pharmaceuticals together with active ingredients, and provide usefulness such as making the pharmaceutical easier to take (masking bitterness and odor, etc.), improving stability, and stably releasing the active ingredient. They also serve to facilitate formulation, and are components that can be used in pharmaceutical solid preparations, such as excipients, disintegrants, binders, lubricants, flow agents, coating agents, colorants, and gloss agents. By "substantially free" it is meant that the additive contains a lower proportion of reducing sugars than is appropriate when used. The content of the reducing sugar is preferably 0.9 mol % or less, and more preferably 0.7 mol % or less, in terms of the ratio (mol %) to the total amount of mirogabalin besylate in the pharmaceutical solid formulation of the present invention. By controlling the content of reducing sugar, the amount of related substances produced can be reduced. The content of the related substances relative to the total amount of the pharmaceutical solid preparation of the present invention is preferably less than 0.24%, more preferably less than 0.20%, and even more preferably less than 0.18%. "Reducing sugar" refers to a sugar that forms an aldehyde or ketone group in a basic solution. Examples of reducing sugars include glucose, fructose, galactose, maltose, lactose, lactulose, cellobiose, glyceraldehyde, arabinose, mannose, xylose, melibiose, maltotriose, and the like, and hydrates thereof. The term "excipient" is defined in general reference books on formulations (for example, "Revised Pharmaceutical Additives Handbook," Yakuji Nipposha, February 28, 2007) and refers to ingredients added to formulations such as tablets to achieve a certain size or concentration. Examples of such sugars include ammonium alginate, calcium carbonate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, tricalcium phosphate, calcium sulfate, crystalline cellulose, powdered cellulose, silicified crystalline cellulose, cellulose acetate, dextrates, dextrin, dextrol, erythritol, ethyl cellulose, fructose, glyceryl palmitostearate, isomalt, kaolin, lactitol, lactose monohydrate, anhydrous lactose, spray-dried lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, polymethacrylate, simethicone, sodium chloride, sorbitol, starch, pregelatinized starch, white sugar, sugar for compression, sugar for confectionery, white sugar spherical granules, sulfobutyl ether β-cyclodextrin, talc, trehalose, and xylitol. Particularly preferred is mannitol. The content of mannitol used in the present invention is preferably 50-90% by weight, more preferably 75-85% by weight, based on the total weight of the uncoated tablet. The term "disintegrant" is described in general reference books on formulations (e.g., "Revised Pharmaceutical Additives Handbook," Yakuji Nipposha, February 28, 2007), and refers to an ingredient added for the purpose of absorbing moisture in the body, expanding, etc., and disintegrating tablets, etc., to facilitate the release of active ingredients. Examples include alginic acid, calcium alginate, carboxymethylcellulose (carmellose), carboxymethylcellulose calcium (carmellose calcium), sodium carboxymethylcellulose, crystalline cellulose, powdered cellulose, chitosan, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, low-substituted hydroxypropylcellulose, hydroxypropyl starch, magnesium aluminum methylcellulose silicate, polacrilin potassium, povidone, sodium alginate, sodium starch glycolate, starch, and pregelatinized starch, and particularly preferred are carmellose and carmellose calcium. The content of carmellose or carmellose calcium used in the present invention is preferably 2-20% by weight, more preferably 5-15% by weight, based on the total weight of the uncoated tablet. In the present invention, in addition to excipients and disintegrants, any components generally used in formulations, such as binders, lubricants, flow agents, coating agents, colorants, and gloss agents, may be used within the scope that does not impair the effects of the present invention. Examples of the "binder" include one or a combination of two or more selected from gum arabic, sodium alginate, carboxyvinyl polymer, gelatin, dextrin, pectin, sodium polyacrylate, pullulan, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and macrogol. The "lubricant" may be one or a combination of two or more selected from magnesium stearate (e.g., a product conforming to the Japanese Pharmacopoeia), calcium stearate (e.g., a product conforming to the Japanese Pharmacopoeia), sodium stearyl fumarate (e.g., a product conforming to the Pharmaceutical Additives Standards), and talc (e.g., a product conforming to the Japanese Pharmacopoeia). Magnesium stearate is particularly preferred. The "fluidizing agent" may be one or a combination of two or more selected from the group consisting of hydrous silicon dioxide, light anhydrous silicic acid, and talc. The "coating agent" is a coating agent that coats the surface of a plain tablet, the surface of a powdered drug (the surface of a crystal), or the granule surface of a granulated drug, and examples thereof include one or a combination of two or more selected from hypromellose, polyethylene glycol, ethyl cellulose, aminoalkyl methacrylate copolymer E, methacrylic acid copolymer L, dry methacrylic acid copolymer LD, methacrylic acid copolymer LD, methacrylic acid copolymer S, aminoalkyl methacrylate copolymer RS, aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer, polyvinyl acetal-diethylaminoacetate, and polyvinyl acetate resin. Examples of the "coloring agent" include food dyes such as Food Yellow No. 5, Food Red No. 2, and Food Blue No. 2; and one or a combination of two or more selected from food lake dye, yellow ferric oxide, ferric oxide, titanium oxide, β-carotene, and riboflavin. A "solid dosage form" includes any formulation used by those skilled in the art to deliver one or more pharma- ceutical active ingredients in a solid form to a patient. Suitable solid formulations are well known to those skilled in the art, and examples of the solid formulation of the present invention include, but are not limited to, tablets (including sublingual tablets and tablets that disintegrate in the mouth), capsules (including soft capsules and microcapsules), granules, pills, and lozenges. As the solid formulation of the present invention, tablets are suitable. The solid preparation of the present invention can be manufactured by any method commonly used and known to those skilled in the art of pharmaceutical formulation technology, and is not particularly limited thereto. Examples of suitable methods are those disclosed in publications such as Powder Technology and Pharmaceutical Processes [D. Chulia et al., Elsevier Science Pub. Co. (December 1, 1993)]. (Method of manufacturing pharmaceutical tablets) The manufacturing method of the tablets is as follows: (1) Direct compression, in which the active ingredient and additives are mixed and compressed in a tablet press. (2) The semi-direct compression method, in which the additives are granulated, mixed with the drug, and compressed into a mold. (3) Dry granulation compression method in which active ingredients and additives are granulated into granules using a dry method, then lubricants and other additives are added and compressed to form the granules. (4) A wet granulation compression method in which the active ingredient and additives are granulated into granules using a wet method, a lubricant is added thereto, and the granules are then compressed and molded. As the granulation method, means such as fluidized bed granulation, high speed stirring granulation, melting granulation, etc. can be used. As a method for producing the tablets of the present invention, a method in which a mixed powder of the active ingredients is directly compressed to prepare tablets without granulating the powder of the active ingredients is preferable. In the direct compression method, the active ingredient is mixed with one or more pharma- ceutically acceptable excipients in a suitable mixer and then transferred directly to a compression machine and pressed into tablets. Other conventional methods such as wet granulation and dry granulation can also be used. Furthermore, the tablet of the present invention may be provided with at least one layer of film coating. When film coating is desired, film coating forming equipment of the type well known in the art can be used. Suitable film coating bases include sugar coating bases, hydrophilic coating bases, enteric coating bases and sustained release coating bases. The "sugar-coating base" includes, for example, sucrose, and may further include one or more combinations of additives such as talc, precipitated calcium carbonate, calcium phosphate, calcium sulfate, gelatin, gum arabic, polyvinylpyrrolidone, and pullulan. Examples of the "hydrophilic film base" include cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methylcellulose (e.g., a premix containing hydroxypropyl methylcellulose as a main component, which is commercially available from Japan Colorcon LLC as OPADRY (registered trademark), etc.), hydroxyethyl cellulose, methylhydroxyethyl cellulose, and sodium carboxymethyl cellulose; synthetic polymers such as polyvinyl acetal diethylamino acetate, aminoalkyl methacrylate copolymer, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, and macrogol; and polysaccharides such as pullulan, which can be used alone or in combination of two or more thereof. More preferred is OPADRY (registered trademark), which contains hydroxypropyl methylcellulose as a main component. As the "enteric coating base", for example, cellulose derivatives such as hydroxypropyl methylcellulose, phthalate hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethyl cellulose and cellulose acetate phthalate; acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S; and natural substances such as shellac can be used alone or in combination of two or more thereof. As the "sustained release coating base", one or more of cellulose derivatives such as ethyl cellulose; and acrylic acid derivatives such as aminoalkyl methacrylate copolymer RS ​​and ethyl acrylate-methyl methacrylate copolymer emulsion can be used in combination. Typically, a premix such as OPADRY®, which is based on hydroxypropyl methylcellulose, is used as the film coating, and typically contains suitable pharma- ceutically acceptable additives such as plasticizers, excipients, lubricants, opacifiers, colorants, or preservatives, as required. For example, the tablet of the present invention can be produced by the production method described below. The active ingredient, mirogabalin besylate, is pulverized to adjust the particle size, and then excipients and / or disintegrants are added and mixed. The mixture is sieved using a granulator, a lubricant is added, and the mixture is further mixed and compressed using a tablet press to obtain uncoated tablets. The obtained plain tablets are, if necessary, coated with a coating device. The present invention will be described in more detail below with reference to examples. However, the following examples are for the purpose of illustrating the present invention, and the present invention should not be construed as being limited to these examples. (Test Example 1) Effects of adding reducing sugar to excipient (1) Sample preparation methods in Examples 1 to 3 D-mannitol and D-glucose that had been ground in advance in a mortar and pestle were weighed out in the mixing ratio shown in Table 1, mixed in a 13K bottle for 5 minutes, and then sieved. Mirogabalin besylate and D-mannitol to which D-glucose had been added were weighed out in the mixing ratio shown in Table 1, mixed in an 8K bottle for 5 minutes, and then sieved to obtain a sample. 1) PEARLITOL (registered trademark) 100SD: Roquette Freres 2) D(+)-Glucose: Fujifilm Wako Pure Chemical Corporation (2) Evaluation method and results The sample was left at 60°C in a sealed bottle for one week, and the amount of related substances was measured by HPLC (Aquity UPLC I-class, Waters) under the conditions shown in Table 2 (the relative retention time of the related substances was 1.8). The results are shown in Table 3. Only in the sample in which D-mannitol containing added D-glucose was used, the amount of related substances increased by more than 0.05%. In addition, a tendency for the amount of related substances to increase depending on the amount of D-glucose was observed. (Test Example 2) Effects of containing reducing sugar in excipient (1) Sample preparation methods in Examples 4 to 9 Mirogabalin besylate and D-mannitol from different production lots were weighed out in the mixing ratio shown in Table 4, mixed in an 8K bottle for 5 minutes, and then sieved to obtain a sample of Formulation 1. Mix tocopherol and crystalline cellulose in a ratio of 1:9 using a high-speed mixing granulator to disperse the tocopherol 10 times. Mirogabalin besylate, D-mannitol, carmellose calcium, pre-sieved citric acid hydrate, 10x powdered tocopherol, magnesium aluminometasilicate, and OPADRY (registered trademark) were weighed out in the proportions shown in Table 4, mixed in an 8K bottle for 5 minutes, and then sieved to obtain a sample of formulation 2. 1) PEARLITOL (registered trademark) 100SD: Roquette Freres 2) Japanese Pharmacopoeia Tocopherol: Mitsubishi Chemical Corporation, CEOLUS (registered trademark) UF-702: Asahi Kasei Corporation 3) ECG-505: Gotoku Pharmaceutical Co., Ltd. 4) Neusilin US2: Fuji Chemical Industry Co., Ltd. 5) Citric acid monohydrate powder EMPROVE ESSENTIAL:Merck KGaA 6) Magnesium stearate (vegetable-based): Taihei Chemical Industry Co., Ltd. 7) OPADRY® 01A440004 (a coating premix consisting of hypromellose, titanium dioxide, talc, yellow ferric oxide and ferric oxide): Colorcon Japan LLC (2) Evaluation method and results ​Each sample was left at 60°C in a sealed bottle for one week, and the amount of related substances was measured by HPLC (Aquity UPLC I-class, Waters) under the conditions shown in Table 2. In addition, the amount of reducing sugar in the D-mannitol used in the preparation of each sample was measured using a spectrophotometer (UV-2550, Shimadzu Corporation). The results are shown in Table 5. When the amount of reducing sugar in the D-mannitol used exceeded 0.01%, the amount of related substances increased by more than 0.05% after storage for 1 week under the sealed condition at 60°C. (Test Example 3) Correlation between reducing sugars contained in D-mannitol and the production of related substances (1) Sample preparation method of Example 10 Mix tocopherol and crystalline cellulose in a ratio of 1:9 using a high-speed mixing granulator to disperse the tocopherol 10 times. Mirogabalin besilate, D-mannitol, carmellose calcium, magnesium aluminometasilicate, citric acid hydrate, and 10x tocopherol powder were weighed out in the mixing ratio shown in Table 6, mixed in a tumble mixer, sieved through a screening mill, magnesium stearate was added, and the mixture was mixed in a tumble mixer to obtain a mixed powder for tableting. The powder mixture for tableting is compressed in a tablet press to produce plain tablets. Using a pan coating machine, a coating solution consisting of OPADRY® and water is sprayed onto the uncoated tablets. After spraying, the tablets are dried to obtain film-coated tablets with a coating layer weight of 3-4% of the uncoated tablets. The film-coated tablets are filled into a heat-formed PTP film, which is then heat-sealed with a PTP lid, and the sealed product is then cut into specimens. 1) PEARLITOL (registered trademark) 100SD: Roquette Freres 2) Japanese Pharmacopoeia Tocopherol: Mitsubishi Chemical Corporation, CEOLUS (registered trademark) UF-702: Asahi Kasei Corporation 3) ECG-505: Gotoku Pharmaceutical Co., Ltd. 4) Neusilin US2: Fuji Chemical Industry Co., Ltd. 5) Citric acid monohydrate powder EMPROVE ESSENTIAL:Merck KGaA 6) Magnesium stearate (vegetable-based): Taihei Chemical Industry Co., Ltd. (2) Evaluation method and results The samples were left in aluminum bags containing desiccant at 40°C and 75% RH for 6 months, after which the amount of related substances was measured using HPLC (Aquity UPLC I-class, Waters) under the conditions shown in Table 2. The reducing sugar content of the D-mannitol used in the preparation of the samples was measured using a spectrophotometer (UV-2550, Shimadzu Corporation). Table 7 shows the relationship between the amount of related substances in the sample after storage for 6 months at 40°C, 75% RH / aluminum bag containing a desiccant and the ratio (mol%) of reducing sugars in D-mannitol to mirogabalin besilate in the formulation. The two showed a high correlation with a correlation coefficient of 0.99 or higher. From Table 7, if the ratio (mol%) of reducing sugars in D-mannitol to mirogabalin besilate in one tablet is 0.9 mol% or less, more preferably 0.7 mol% or less, the amount of related substances is set to be within the range of 0.9 mol% or less, as specified in "Revision of the Guidelines on Impurities in Pharmaceuticals Containing New Active Ingredients (Notification No. 0624001 of the Pharmaceutical and Medical Devices Evaluation and Licensing Division dated June 24, 2003)" This indicates that the impurity concentration can be suppressed to below the standard value of "0.2% threshold for determining the impurity structure" (0.15 or more and less than 0.25) described in the (https: / / www.pmda.go.jp / files / 000156298.pdf) The present invention makes it possible to suppress the generation of related substances to below the standard value "threshold value of 0.2% requiring structural determination of impurities" (0.15 or more and less than 0.25) described in "Revision of the Guidelines on Impurities in Drug Formulations Containing New Active Ingredients (PMDA Notification No. 0624001 dated June 24, 2003)" (https: / / www.pmda.go.jp / files / 000156298.pdf). (Production example) The following is an example of the production of the tablet of the present invention. This example is not to be construed as limiting the present invention. (1) Mixing / sieving Mirogabalin besylate, D-mannitol, and carmellose calcium were weighed out in the mixing ratio shown in Table 8 below, and mixed for 2 minutes at 31 rpm using a V-type mixer (60 L). The mixture was sieved at 600 rpm using a Comil (QC-194S, Φ1.143 mm, QUADRO) to obtain a sieved powder. Next, magnesium stearate was weighed out in the blending ratio shown in Table 8, added to the sieved powder, and mixed for 6 minutes at 31 rpm using a V-type mixer (60 L). (2) Tablet compression Using a tablet press (Virgo, Kikusui Seisakusho), tablets were made to a mass of 200 mg and pressed at a tableting pressure of approximately 12 kN to obtain plain tablets (containing 2.5% mirogabalin besylate as free form, oblong tablets, 10.6 x 5.6 mm). (3) Coating OPADRY (registered trademark) was dispersed in purified water (12.5 w / w%) using a mixer (Z-2200, Tokyo Rika Kikai) and sieved through a 100 mesh sieve to prepare a coating liquid. For uncoated tablets, a coating device (DRC300, Powrex) was used, with an inlet air temperature of 70°C and an inlet air volume of 1.0 m 3 / min, spray rate of about 7 g / min, pan rotation speed of 20 rpm, and exhaust temperature end point of about 36°C, to obtain coated tablets. 1) Parteck® M100: Merck KGaA 2) ECG-505: Gotoku Pharmaceutical Co., Ltd. 3) Parteck® LUB: Merck KGaA 4) Japan Colorcon LLC

Claims

1. Contains mirogabalin or a pharmaceutically acceptable salt thereof, It contains one or more pharmaceutically acceptable additives and at least The one or more pharmaceutically acceptable additives include: Contains an excipient and / or a disintegrant, A pharmaceutical solid formulation that is substantially free of reducing sugars.

2. Contains mirogabalin or a pharmaceutically acceptable salt thereof, It contains one or more pharmaceutically acceptable additives and at least The one or more pharmaceutically acceptable additives include: Contains an excipient and / or a disintegrant, A pharmaceutical solid preparation in which the ratio of reducing sugars contained in one pharmaceutical solid preparation to mirogabalin or a pharmaceutically acceptable salt thereof is 0.9 mol % or less.

3. 3. The solid formulation according to claim 2, wherein the ratio of reducing sugars contained in one solid formulation to mirogabalin or a pharmaceutically acceptable salt thereof is 0.7 mol % or less.

4. Contains mirogabalin or a pharmaceutically acceptable salt thereof, It contains one or more pharmaceutically acceptable additives and at least The one or more pharmaceutically acceptable additives include: Contains an excipient and / or a disintegrant, A pharmaceutical solid dosage form in which the ratio of related substances contained in one solid dosage form to mirogabalin or a pharmaceutically acceptable salt thereof is less than 0.24%.

5. 5. The solid formulation according to claim 4, wherein the ratio of the related substance contained in one solid formulation to mirogabalin or a pharmaceutically acceptable salt thereof is less than 0.20%.

6. 5. The solid formulation according to claim 4, wherein the ratio of the related substance contained in one solid formulation to mirogabalin or a pharmaceutically acceptable salt thereof is less than 0.18%.

7. 7. The solid formulation according to claim 4, wherein the related substances are measured after the solid formulation is subjected to an accelerated test under conditions of 40°C and 75% RH for 6 months.

8. 4. The solid formulation according to claim 1, wherein the reducing sugar is one or more selected from the group consisting of glucose, fructose, galactose, maltose, lactose, lactulose, cellobiose, glyceraldehyde, arabinose, mannose, xylose, melibiose, maltotriose, and hydrates thereof.

9. 7. The solid formulation according to claim 1, which contains mannitol as an excipient.

10. 7. The solid formulation according to claim 1, comprising carmellose or carmellose calcium as a disintegrant.

11. 7. The solid formulation according to claim 1, wherein the solid formulation is a tablet.

12. 7. The solid formulation according to claim 1, wherein the mirogabalin or a pharmaceutically acceptable salt thereof is mirogabalin besylate.

13. 3. The method for producing a solid formulation according to claim 2, wherein the ratio of reducing sugars to mirogabalin or a pharmaceutically acceptable salt thereof in one solid formulation is 0.9 mol % or less.

14. 4. The method for producing a solid formulation according to claim 3, wherein the ratio of reducing sugars to mirogabalin or a pharmaceutically acceptable salt thereof in one solid formulation is 0.7 mol % or less.

15. 15. The method according to claim 13 or 14, wherein the reducing sugar is any one selected from the group consisting of glucose, fructose, galactose, maltose, lactose, lactulose, cellobiose, glyceraldehyde, arabinose, mannose, xylose, melibiose, maltotriose, and hydrates thereof.

16. 15. The method of claim 13 or 14, wherein the excipient is mannitol.

17. 15. The method according to claim 13 or 14, wherein the disintegrant is carmellose or carmellose calcium.

18. 15. The method according to claim 13 or 14, wherein the solid formulation is a tablet.

19. 15. The method of claim 13 or 14, wherein the mirogabalin or a pharmaceutically acceptable salt thereof is mirogabalin besylate.