Pharmaceutical composition containing lacosamide

Abstract

To provide a pharmaceutical composition containing lacosamide in which decomposition of lacosamide is suppressed due to storage.SOLUTION: A pharmaceutical composition comprises lacosamide and does not comprise sodium lauryl sulfate. The pharmaceutical composition may not comprise light anhydrous silicic acid. The pharmaceutical composition may comprise hydrated silicon dioxide and / or magnesium aluminometasilicate. In this case, the total content of the hydrated silicon dioxide and / or the magnesium aluminometasilicate may be 1 mass% or less based on the total amount of the pharmaceutical composition.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition containing lacosamide. [Background technology]

[0002] Lacosamide ((2R)-2-acetamido-N-benzyl-3-methoxypropanamide) is an active ingredient in a drug used to treat epilepsy, and is a compound represented by the following structural formula. [ka]

[0003] Vimpat Dry Syrup 10% (Pfizer Inc.) is a formulation containing lacosamide. Vimpat Dry Syrup 10% is a dry syrup containing granules containing lacosamide, D-mannitol, crospovidone, hydroxypropyl cellulose, sucralose, sodium lauryl sulfate, and a flavoring, and light anhydrous silicic acid (Non-Patent Document 1). [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Vimpat Dry Syrup 10% Package Insert Summary of the Invention [Problem to be solved by the invention]

[0005] The present inventors have found that the active ingredient lacosamide in Vimpat Dry Syrup 10% decomposes during storage, producing related substances. Therefore, an object of the present invention is to provide a lacosamide-containing pharmaceutical composition in which the decomposition of lacosamide during storage is suppressed. [Means for solving the problem]

[0006] The present inventors have conducted extensive research to solve the above problems and have found that sodium lauryl sulfate, one of the additives contained in Vimpat Dry Syrup 10%, promotes the production of related substances due to the decomposition of lacosamide.

[0007] The present invention was completed based on the above findings, and provides the following [1] to [6]. [1] A pharmaceutical composition (excluding tablets) containing lacosamide but not sodium lauryl sulfate. [2] The pharmaceutical composition according to [2], which does not contain light anhydrous silicic acid. [3] The pharmaceutical composition according to [2], which does not contain any of light anhydrous silicic acid, hydrous silicon dioxide, and magnesium aluminometasilicate, or contains hydrous silicon dioxide and / or magnesium aluminometasilicate. [4] The pharmaceutical composition according to [3], wherein the total content of hydrous silicon dioxide and / or magnesium aluminometasilicate, when contained, is 1% by mass or less based on the total amount of the pharmaceutical composition. [5] The pharmaceutical composition according to [1] or [2], wherein the pharmaceutical composition is a dry syrup. [6] A method for suppressing the decomposition of lacosamide or the production of related substances during storage by making a pharmaceutical composition containing lacosamide free of sodium lauryl sulfate. [Effects of the Invention]

[0008] Since the pharmaceutical composition of the present invention does not contain sodium lauryl sulfate, the decomposition of lacosamide is suppressed. In recent years, there has been concern that lacosamide may decompose during normal distribution and storage in the extremely hot weather. However, since the pharmaceutical composition of the present invention suppresses the decomposition of lacosamide, it can be distributed and stored under normal conditions.

[0009] Here, dry syrups are required to be free-flowing during production, storage, and use, and therefore, it may be desirable to mix granules with a fluidizer. However, the present inventors have found that, depending on the type of fluidizer, aggregates may form when dissolved or suspended in water at the time of administration. In this regard, when the pharmaceutical composition of the present invention contains hydrous silicic acid dioxide and / or magnesium aluminometasilicate as a fluidizer, no aggregates are formed when dissolved or suspended in water, resulting in a uniform suspension. If aggregates form after dissolution or suspension in water, resulting in an inhomogeneous suspension, consumers may have a negative impression. However, using hydrous silicic acid dioxide and / or magnesium aluminometasilicate as a fluidizer can avoid such aggregation. DETAILED DESCRIPTION OF THE INVENTION

[0010] The present invention will be described in detail below. The pharmaceutical composition of the present invention contains lacosamide but does not contain sodium lauryl sulfate. In the present invention, the term "does not contain sodium lauryl sulfate" includes cases where unavoidable impurities are present. The concentration of lacosamide may be 2% by mass or more, 4% by mass or more, or 8% by mass or more, and 9% by mass or less, 10% by mass or less, or 12% by mass or less, based on the total amount of the pharmaceutical composition, with 10% by mass being preferred.

[0011] The pharmaceutical composition of the present invention does not include tablets, and examples of dosage forms include solid preparations such as powders, granules, fine granules, capsules (hard capsules, soft capsules), dry syrup, films, lozenges, chewing gum, etc. Among these, dry syrup, which is taken after dissolving or suspending, is preferred.

[0012] The pharmaceutical composition of the present invention may contain various additives added to the pharmaceutical composition. Such additives include excipients, binders, disintegrants, lubricants, fluidizing agents, glossing agents, stabilizers, antioxidants, emulsifiers, surfactants, solubilizers, suspending agents, dispersing agents, buffers, pH adjusters, thickening agents, adsorbents, colorants, flavoring agents, sweeteners, fragrances, preservatives or antiseptics, foaming agents, antifoaming agents, coating agents, plasticizers, etc. One or more additives may be used.

[0013] Excipients include erythritol, lactose and crystalline cellulose spherical granules, candy powder, gum arabic, powdered gum arabic, pregelatinized starch, partially pregelatinized starch, starch (wheat starch, rice starch, potato starch, corn starch), isomalt hydrate, kaolin, reduced palatinose, xylitol, L-glutamine, croscarmellose sodium, crospovidone, silicic acid-treated crystalline cellulose, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, synthetic hydrotalcite, titanium oxide, β-cyclodextrin, aluminum hydroxide gel, refined sucrose, refined sucrose spherical granules, gelatin, D-sorbitol, talc, medium-chain fatty acid triglycerides, Precipitated calcium carbonate, low-substituted hydroxypropyl cellulose, sodium starch glycolate (sodium carboxymethyl starch), trehalose hydrate, lactose hydrate, white sugar, white sugar-starch spherical granules, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, glucose, pullulan, polyoxyethylene hydrogenated castor oil (N), polyoxyethylene (N) polyoxypropylene (N) glycol, macrogol (macrogol 4000, macrogol 6000), maltitol, D-mannitol, anhydrous lactose, anhydrous calcium hydrogen phosphate, magnesium aluminometasilicate, glycerin monostearate, calcium hydrogen phosphate, calcium hydrogen phosphate hydrate, etc.

[0014] Binders include cellulose binders (ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hypromellose, carboxymethylethyl cellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylethyl cellulose, calcium carboxymethylethyl cellulose, hydroxyethyl cellulose, hypromellose acetate succinate, hypromellose phthalate), gum arabic, powdered gum arabic, pregelatinized starch, partially pregelatinized starch, starch (wheat starch, rice starch, corn starch, potato starch), hydroxypropyl starch, sodium alginate, gelatin, low-substituted hydroxypropyl cellulose, dextrin, sodium starch glycolate (sodium carboxymethyl starch), pullulan, macrogol (macrogo Macrogol 400, Macrogol 4000, Macrogol 6000), ethyl acrylate-methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer (aminoalkyl methacrylate copolymer E, etc.), ammonioalkyl methacrylate copolymer (aminoalkyl methacrylate copolymer RS), carboxyvinyl polymer, agar powder, guar gum, copolyvidone, cetanol, shellac, dextrin, pectin, povidone, polyvinyl alcohol, polyvinyl acetal diethylaminoacetate, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, polyvinyl alcohol (partially saponified), polyvinyl alcohol-polyethylene glycol graft copolymer, methacrylic acid copolymer (dried methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S).

[0015] Disintegrants include starch (wheat starch, rice starch, potato starch, corn starch), sodium starch glycolate (sodium carboxymethyl starch), hydroxypropyl starch, hydroxypropyl cellulose, partially pregelatinized starch, croscarmellose sodium, crospovidone, light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, magnesium aluminum metasilicate, carmellose, carmellose calcium, calcium silicate, sodium lauryl sulfate, etc.

[0016] When the pharmaceutical composition of the present invention contains a disintegrant (particularly, crospovidone), the total concentration of the disintegrant (particularly, the concentration of crospovidone) can be 0.8% by mass or more, 1% by mass or more, 1.2% by mass or more, or 1.5% by mass or more, and can be 8% by mass or less, 7% by mass or less, 6% by mass or less, or 5.5% by mass or less, based on the total amount of the pharmaceutical composition.

[0017] Lubricants include talc, glyceryl monostearate, dimethylpolysiloxane (for oral use), sucrose fatty acid esters, stearic acid, stearates (calcium stearate, magnesium stearate, sodium stearyl fumarate), and dl-leucine.

[0018] Examples of the fluidizing agent include calcium silicate, talc, light anhydrous silicic acid, hydrous silicon dioxide, synthetic aluminum silicate, and magnesium aluminometasilicate.

[0019] Examples of glossing agents include carnauba wax, refined paraffin-carnauba wax mixed wax, white beeswax, and refined shellac.

[0020] Stabilizers include meglumine, citric acid hydrate, sodium benzoate, sodium edetate hydrate, dibutylhydroxytoluene, xylitol, D-sorbitol, lactose hydrate, D-mannitol, sodium citrate hydrate, tartaric acid, anhydrous citric acid, DL-malic acid, talc, light anhydrous silicic acid, magnesium aluminum metasilicate, glycerin monostearate, sucrose fatty acid ester, stearic acid, sodium lauryl sulfate, macrogol (Macrogol 400, Macrogol 4000, etc.), carboxyvinyl polymer, polyvinyl alcohol, etc. Ingredients include methylparaben, methylparaben, methylparaben, methylparaben (vitamin B1), methylparaben (vitamin B2), ...2), methylparaben (vitamin B1), methylparaben (vitamin B2), methylparaben (vitamin B2), methylparaben (vitamin B1), methylparaben (vitamin B2), methylparaben (vitamin B2), methylparaben (vitamin B1), methylparaben (vitamin B2), methylparaben (vitamin B2), methylparaben (vitamin B2), methylparaben (vitamin B2), methylparaben (vitamin B3), methylparaben (vitamin B1), methylparaben (vitamin B2), methylparaben (vitamin B2), methylparaben (vitamin B3), methylparaben (vitamin B1), methylparaben (vitamin B2), methylparaben (vitamin B2), methylparaben (vit

[0021] Antioxidants include anhydrous citric acid, citric acid hydrate, soybean lecithin, dibutylhydroxytoluene, tocopherol, and propyl gallate.

[0022] Examples of emulsifiers include glycerin monostearate, polyoxyethylene hydrogenated castor oil (N), polysorbate 80, medium-chain fatty acid triglyceride, soybean lecithin, and lauromacrogol.

[0023] Examples of surfactants include glycerin monostearate, polyoxyethylene hydrogenated castor oil (N), polysorbate 80, lauromacrogol, macrogol (such as macrogol 400), polyoxyethylene (N) polyoxypropylene (N) glycol, and the like.

[0024] Solubilizers include polyoxyethylene hydrogenated castor oil (N), polysorbate 80, lauromacrogol, polyoxyethylene (N) polyoxypropylene (N) glycol, medium-chain fatty acid triglyceride, soybean lecithin, meglumine, D-mannitol, sodium citrate hydrate, anhydrous citric acid, sucrose fatty acid ester, macrogol (Macrogol 4000, Macrogol 6000, etc.), polyvinyl alcohol (partially saponified), L-aspartic acid, L-arginine, sodium hydroxide, sodium bicarbonate, lactic acid, concentrated glycerin, hydroxypropyl cellulose, β-cyclodextrin, glycerin, soybean oil, and triacetin.

[0025] Suspending agents include polyoxyethylene hydrogenated castor oil (N), polysorbate 80, soybean lecithin, sucrose fatty acid esters, macrogol (such as macrogol 4000 and macrogol 6000), sodium hydroxide, hydroxypropyl cellulose, glycerin, D-sorbitol, magnesium aluminum metasilicate, carboxyvinyl polymer, dried aluminum hydroxide gel, xanthan gum, butylated hydroxyanisole, propylene glycol, crystalline cellulose, gum arabic, powdered gum arabic, hypromellose, powdered agar, povidone, methylcellulose, kaolin, carrageenan, carmellose sodium, glycerin fatty acid esters, and magnesium aluminum silicate.

[0026] Dispersing agents include propylene glycol alginate, ethanol, carmellose sodium, citric acid hydrate, sodium citrate hydrate, glycerin, glycerin fatty acid esters, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, crystalline cellulose-carmellose sodium, titanium oxide, sucrose fatty acid esters, stearic acid, magnesium stearate, oleic acid, sorbitan fatty acid esters, low-substituted hydroxypropyl cellulose, dextrin, sodium starch glycolate, corn starch, concentrated glycerin, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, propylene glycol, povidone, polysorbate 80, macrogol (Macrogol 300, Macrogol 4000, etc.), anhydrous sodium citrate, magnesium aluminometasilicate, glycerin monooleate, sorbitan monooleate, aluminum monostearate, glycerin monostearate, sodium lauryl sulfate, lauromacrogol, and calcium hydrogen phosphate hydrate.

[0027] Examples of buffering agents include sodium citrate hydrate, anhydrous citric acid, sodium bicarbonate, lactic acid, citric acid hydrate, sodium benzoate, tartaric acid, DL-malic acid, sodium chloride, acetic acid, sodium acetate hydrate, anhydrous sodium monohydrogen phosphate, L-glutamic acid, and dilute hydrochloric acid.

[0028] Examples of pH adjusters include L-glutamine, sodium citrate hydrate, anhydrous citric acid, sodium bicarbonate, lactic acid, citric acid hydrate, tartaric acid, DL-malic acid, acetic acid, sodium acetate hydrate, anhydrous sodium monohydrogen phosphate, dilute hydrochloric acid, sodium hydroxide, meglumine, succinic acid, and aqueous ammonia.

[0029] Examples of thickening agents include guar gum, hydroxypropyl cellulose, carboxyvinyl polymer, xanthan gum, propylene glycol, hypromellose, carrageenan, carmellose sodium, concentrated glycerin, gelatin, hydroxyethyl cellulose, carob bean gum, α-cyclodextrin, and locust bean gum.

[0030] Examples of the adsorbent include magnesium aluminometasilicate, kaolin, light anhydrous silicic acid, synthetic aluminum silicate, magnesium silicate, precipitated calcium carbonate, and the like.

[0031] Coloring agents include titanium oxide, indigo carmine, yellow ferric oxide, carmine, black iron oxide, ferric oxide, synthetic food colors (food blue No. 1, food blue No. 2 aluminum lake, food yellow No. 4, food yellow No. 4 aluminum lake, food yellow No. 5, food red No. 2, food red No. 3, food red No. 102, etc.), and natural food colors.

[0032] Examples of flavoring agents include erythritol, xylitol, refined sucrose, D-sorbitol, lactose hydrate, sucrose, glucose, D-mannitol, aspartame, cocoa powder, reduced maltose syrup, reduced syrup, licorice, licorice extract, citric acid hydrate, sodium citrate hydrate, L-glutamic acid, succinic acid, saccharin, saccharin sodium hydrate, tartaric acid, sucralose, purified stevia extract, peppermint oil, anhydrous citric acid, l-menthol, and DL-malic acid.

[0033] Sweeteners include xylitol, refined white sugar, D-sorbitol, lactose hydrate, white sugar, glucose, D-mannitol, aspartame, reduced maltose syrup, licorice, licorice extract, saccharin, saccharin sodium hydrate, sucralose, purified stevia extract, maltitol, acesulfame potassium, and thaumatin.

[0034] Flavoring agents include peppermint oil, l-menthol, vanillin, etc.

[0035] Examples of preservatives or antiseptics include citric acid hydrate, sodium benzoate, sodium edetate hydrate, dibutylhydroxytoluene, parahydroxybenzoic acid esters (isobutyl parahydroxybenzoate, isopropyl parahydroxybenzoate, ethyl parahydroxybenzoate, butyl parahydroxybenzoate, propyl parahydroxybenzoate, methyl parahydroxybenzoate, etc.).

[0036] Examples of the foaming agent include hydrogen carbonates (sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), and carbonates (magnesium carbonate, calcium carbonate, etc.).

[0037] Examples of coating agents include water-soluble coating agents such as cellulose-based coating agents, such as methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose), hydroxypropylcellulose phthalate, carboxymethylethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hypromellose phthalate, hypromellose acetate succinate, cellulose acetate, and cellulose acetate phthalate; vinyl polymers such as carboxyvinyl polymer, polyvinyl alcohol, povidone, copolyvidone, and polyvinyl alcohol-polyethylene glycol copolymer; polyoxyethylene-polyoxypropylene glycol; polyethylene glycol (macrogol); methacrylate polymers, and methacrylic acid polymers. Examples of methacrylate polymers or methacrylic acid polymers include aminoalkyl methacrylate copolymer E (Eudragit (registered trademark) E100, EPO, etc.), methacrylic acid copolymer LD (Eudragit L30D-55, L100-55, etc.), methacrylic acid copolymer L (Eudragit L100, etc.), and methacrylic acid copolymer S (Eudragit S100, etc.) manufactured by Rohm.

[0038] Examples of the plasticizer include polyethylene glycol, propylene glycol, glycerin, glycerin fatty acid esters such as triacetin (glycerin triacetate), liquid paraffin, sorbitan monolaurate, monostearin, triethyl citrate, tributyl citrate, diethyl phthalate, dibutyl phthalate, diethyl sebacate, dibutyl sebacate, poloxamer, and polyoxyethylene hydrogenated castor oil.

[0039] The pharmaceutical composition of the present invention preferably does not contain light anhydrous silicic acid. In the present invention, the phrase "does not contain light anhydrous silicic acid" includes cases where unavoidable impurities are present. The pharmaceutical composition of the present invention preferably contains hydrous silicon dioxide and / or magnesium aluminometasilicate. When hydrous silicon dioxide and / or magnesium aluminometasilicate are contained, their total concentration may be greater than 0% by mass, but may be 0.08% by mass or more, 0.1% by mass or more, 0.15% by mass or more, or 0.2% by mass or more, based on the total amount of the pharmaceutical composition. When hydrous silicon dioxide and / or magnesium aluminometasilicate are contained, their total concentration may be 1% by mass or less, 0.7% by mass or less, 0.5% by mass or less, or 0.3% by mass or less, based on the total amount of the pharmaceutical composition. Within these ranges, aggregates due to insoluble residues are unlikely to form when the pharmaceutical composition is dissolved in water. In particular, pharmaceutical compositions that are dissolved or suspended in water and taken, such as dry syrups, and pharmaceutical compositions that may be dissolved or suspended in water and taken, such as granules, fine granules, and powders, preferably do not contain light anhydrous silicic acid, or, if a fluidizing agent is contained, preferably contain hydrous silicon dioxide and / or magnesium aluminometasilicate. Furthermore, as shown in the Examples section, compositions that do not contain any of light anhydrous silicic acid, hydrous silicon dioxide, and magnesium aluminometasilicate are also preferred because they do not or are less likely to form aggregates when dissolved or suspended in water.

[0040] When the pharmaceutical composition of the present invention is in the form of a dry syrup, granules, or fine granules, the hydrous silicon dioxide and magnesium aluminometasilicate may be partly or entirely (particularly entirely) mixed in a powdered state with the granules. Therefore, dry syrup, granules, or fine granules containing hydrous silicon dioxide and / or magnesium aluminometasilicate can be produced by a method comprising the steps of granulating a mixture of lacosamide and additives, and mixing the resulting granules with additives containing hydrous silicon dioxide and / or magnesium aluminometasilicate. Examples of the granulation method include wet granulation such as fluidized bed granulation, stirring granulation, rolling granulation, extrusion granulation, crushing granulation, and kneading granulation; and dry granulation such as flake granulation, briquette granulation, and melt granulation. Among these, wet granulation is preferred, and extrusion granulation is more preferred.

[0041] The maximum diameter of the lacosamide-containing granules can be 0.1 mm or more, 0.5 mm or more, 0.85 mm or more, or 1.4 mm or more, and 1.4 mm or less, 1 mm or less, 0.5 mm or less, 0.3 mm or less, 0.2 mm or less, or 0.1 mm or less. The maximum diameter is a value measured by a sieving method, and refers to the size of the sieve openings through which the granules pass, regardless of the shape of the granules.

[0042] The present invention provides a method for inhibiting the decomposition of lacosamide or the production of related substances during storage by making a pharmaceutical composition containing lacosamide free of sodium lauryl sulfate. In this method, the composition, properties, production method, etc. of the pharmaceutical composition are the same as those explained for the pharmaceutical composition of the present invention. [Example]

[0043] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0044] (1) Lacosamide concentration measurement method The concentration of lacosamide was measured by liquid chromatography under the following conditions. Analysis conditions 1 Column: InertSustain C8, inner diameter 4.6 mm x 250 mm, 5 μm Mobile phase A: Water / methanesulfonic acid mixture (4000:3) Mobile phase B: Acetonitrile / methanesulfonic acid mixture (4000:3) Mobile phase flow rate: 1.2 mL / min Column temperature: 40℃ Detector: 258 nm Time Program [Table 1]

[0045] Analysis conditions 2 Column: InertSustain C8, inner diameter 4.6 mm x 250 mm, 5 μm Mobile phase A: Water / trifluoroacetic acid mixture (1000:1) Mobile phase B: Acetonitrile / methanol / trifluoroacetic acid mixture (2000:2000:1) Mobile phase flow rate: 1.2 mL / min Column temperature: 40℃ Detector: 258 nm Time Program [Table 2]

[0046] Analysis conditions 3 Column: InertSustain C18, inner diameter 4.6 mm x 250 mm, 3 μm Mobile phase A: Water / methanesulfonic acid mixture (1000:1) Mobile phase B: methanol / acetonitrile / methanesulfonic acid mixture (600:400:1) Mobile phase flow rate: 0.8 mL / min Column temperature: 40℃ Detector: 258 nm Time Program [Table 3]

[0047] (2) Evaluation of inhibition of lacosamide degradation 10 g of Vimpat Dry Syrup 10% (UCB Japan Co., Ltd.) was placed in a polyethylene bottle and left to stand under harsh conditions of 55°C and 75% RH for 4 weeks. Liquid chromatography was performed under analytical condition 1 to quantify related substances. The total amount of related substances (%) was calculated as the percentage of the sum of the areas of all peaks relative to the peak area of ​​pure lacosamide. The total amount of related substances was 0% before storage under harsh conditions for 4 weeks, but was 0.4% after storage for 4 weeks.

[0048] Next, to identify the additives in Vimpat Dry Syrup 10% that promote the decomposition of lacosamide, each additive was mixed with lacosamide in powder form, placed in a glass bottle, and left to stand for four weeks under harsh conditions of 55°C and 75% RH. Liquid chromatography was performed under analytical condition 2 to determine the total amount (%) of related substances before and after standing. The mixing ratios of the additives and the total amount of related substances are shown in Table 4. [Table 4] It was revealed that sodium lauryl sulfate accelerates the degradation of lacosamide.

[0049] Next, the amounts of related substances produced in the dry syrup were compared between those containing sodium lauryl sulfate and those not containing sodium lauryl sulfate. Lacosamide, D-mannitol, sucralose, and crospovidone were mixed in a stirring mixer (Earth Technica Co., Ltd., High-Speed ​​Mixer FS-GS-40J), and a solution of hydroxypropyl cellulose and, if sodium lauryl sulfate was included, sodium lauryl sulfate dissolved in water was added. After kneading, the mixture was granulated using an extrusion granulator (Dalton Co., Ltd., Extrusion Granulator Basket Breuser BR-150), dried in a dryer, and sized using a sieve (Dalton Co., Ltd., Power Mill). Light anhydrous silicic acid was added and mixed to produce a dry syrup having the composition shown in Table 5. [Table 5] Each dry syrup obtained was placed in a polyethylene bottle and allowed to stand for 4 weeks under harsh conditions of 55°C and 75% RH. Liquid chromatography was performed under analytical condition 3 before and after standing, and the amount of RRT1.05 was calculated as the percentage (%) of the peak area of ​​the related substance RRT1.05 relative to the peak area of ​​pure lacosamide before and after standing. RRT1.05 is the related substance with the largest peak area among the related substance peaks, and the peak area of ​​RRT1.05 accounts for most of the peak area of ​​the related substances. As shown in Table 5, by removing sodium lauryl sulfate from the dry syrup, the RRT1.05 amount was reduced to below 0.1%, which is the threshold for the amount of related substances that should be reported in the ICH guideline (ICH-Q3B).

[0050] (3) Evaluation of dispersibility during suspension We investigated whether the type of glidant mixed with lacosamide-containing granules affects the dispersibility of the dry syrup. Lacosamide, D-mannitol, sucralose, and crospovidone were mixed in a stirring mixer (Earth Technica Co., Ltd., High-Speed ​​Mixer FS-GS-40J), to which a solution of hydroxypropyl cellulose in water was added and kneaded, and the mixture was then granulated using an extrusion granulator (Dalton Co., Ltd., Extrusion Granulator Basket Breezer BR-150), dried in a dryer, and sized using a sieve (Dalton Co., Ltd., Power Mill). Light anhydrous silicic acid, hydrous silicon dioxide, or magnesium aluminometasilicate and a flavoring were added and mixed to produce dry syrups with the compositions shown in Table 6. At room temperature (25°C), 0.5 g of the resulting dry syrup and 20 mL of purified water at room temperature were placed in a 30 mL glass bottle, which was then inverted 10 times and allowed to stand for 5 minutes. At this point, the presence of aggregates was visually confirmed. The glass bottle was then inverted again 2-3 times (resuspension), and immediately placed in a 10 mm cell. The light transmittance was measured under the following conditions. <Transmittance measurement conditions> Measuring equipment: UV-2600 (Shimadzu Corporation) Measurement wavelength: 660nm Measurement time: 10 seconds Sampling pitch: 1 second Number of data points: 11

[0051] Table 6 shows the light transmittance and the presence or absence of aggregates. [Table 6] The incorporation of hydrous silicon dioxide or magnesium aluminometasilicate did not change the transmittance (comparison between Examples 2 to 4 and Example 6). On the other hand, the incorporation of light anhydrous silicic acid increased the transmittance (comparison between Example 5 and Example 6). The more the particles aggregate, the more water regions where no particles exist increase, allowing light to pass through more easily, and therefore the transmittance increases. Furthermore, the less the particles aggregate, the more light is scattered, resulting in a smaller measured transmittance. Therefore, it can be seen that the incorporation of hydrous silicon dioxide or magnesium aluminometasilicate did not cause aggregation, but the incorporation of light anhydrous silicic acid caused aggregation. Furthermore, light anhydrous silicic acid produced aggregates large enough to be seen with the naked eye, but hydrous silicon dioxide and magnesium aluminometasilicate did not produce aggregates large enough to be seen with the naked eye, as was the case when no fluidizing agent was added. The present inventors have found that crospovidone is the cause of the aggregates, and have found that using hydrous silicon dioxide or magnesium aluminometasilicate instead of light anhydrous silicic acid is compatible with crospovidone and can suppress aggregation.

[0052] Furthermore, each of the dry syrup preparations of Examples 2 to 4 in Table 6 was placed in a polyethylene bottle and allowed to stand for 4 weeks under harsh conditions of 55°C and 75% RH. After standing for 4 weeks, the total amount of related substances was measured by the method described in the section "(1) Evaluation of inhibition of lacosamide degradation," and the result was less than 0.1% for all preparations.

[0053] Next, dry syrups having the compositions shown in Table 7 were prepared in the same manner as in "(3) Evaluation of dispersibility when suspended," except that lacosamide was not added, and the dispersibility when suspended was evaluated in the same manner as in "(3) Evaluation of dispersibility when suspended." [Table 7] Regardless of the concentration of hydrous silicon dioxide or magnesium aluminometasilicate, the transmittance was approximately the same as that of Reference Example 7 in which no fluidizing agent was added, and no aggregates were observed visually. [Industrial Applicability]

[0054] Since the decomposition of lacosamide in the pharmaceutical composition of the present invention is inhibited, it can be distributed and stored under normal management conditions even during the recent extreme heat, and therefore has high commercial value.

Claims

1. A pharmaceutical composition (excluding tablets) comprising lacosamide and not containing sodium lauryl sulfate.

2. The pharmaceutical composition of claim 1 , which does not contain light anhydrous silicic acid.

3. 3. The pharmaceutical composition according to claim 2, which does not contain any of light anhydrous silicic acid, hydrous silicon dioxide, and magnesium aluminometasilicate, or which contains hydrous silicon dioxide and / or magnesium aluminometasilicate.

4. 4. The pharmaceutical composition according to claim 3, wherein the total content of hydrous silicon dioxide and / or magnesium aluminometasilicate, when contained, is 1 mass% or less based on the total amount of the pharmaceutical composition.

5. The pharmaceutical composition according to claim 1 or 2, which is a dry syrup.

6. A method for suppressing the decomposition of lacosamide or the production of related substances during storage by making a pharmaceutical composition containing lacosamide free of sodium lauryl sulfate.

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