Rasagiline mesylate-containing pharmaceutical composition

Abstract

The present invention provides a pharmaceutical composition containing rasagiline mesylate in which the degradation of rasagiline mesylate during storage is suppressed. [Solution] A pharmaceutical composition comprising rasagiline mesylate and carmellose and / or carmellose calcium. This composition may further include (i) calcium stearate and / or (ii) a combination of stearic acid and talc.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition containing rasagiline mesylate.

Background Art

[0002] Rasagiline mesylate (N-[(1R)-indan-1-yl]propin-3-amine monomethanesulfonate) is an active ingredient of a therapeutic agent for Parkinson's disease and is a compound represented by the following structural formula.

Chemical

[0003] As a preparation containing rasagiline mesylate, Azilect tablets of 1 mg and 0.5 mg are commercially available. Azilect tablets are tablets containing rasagiline mesylate, D-mannitol, corn starch, partially pregelatinized starch, stearic acid, talc, and light anhydrous silicic acid (Non-Patent Document 1).

[0004] Azilect tablets have poor storage stability of rasagiline mesylate, and related substances are likely to occur under harsh conditions. Attempts have been made to improve the storage stability of rasagiline mesylate in tablets. For example, Patent Document 1 discloses that by blending a pentavalent or hexavalent alcohol such as mannitol, xylitol, or sorbitol in an amount of 60% by weight or more based on the total amount of the tablets in tablets containing rasagiline mesylate, the storage stability of rasagiline mesylate is improved. However, the tablets of Patent Document 1 do not have practically sufficient stability of rasagiline mesylate.

[0005] There is also Patent Document 2 as a document that discloses a preparation containing rasagiline mesylate. Patent Document 2 teaches that by blending a lubricant such as sodium stearyl fumarate or magnesium stearate in a preparation containing rasagiline mesylate, the disintegration property of the preparation is improved.

Prior Art Documents

Patent Documents

[0006] [Patent Document 1] Patent No. 4108750 [Patent Document 2] Japanese Patent Publication No. 2024-37149 [Non-patent literature]

[0007] [Non-Patent Document 1] Azilect Tablets 1mg / 0.5mg Package Insert [Overview of the project] [Problems that the invention aims to solve]

[0008] The object of this invention is to provide a pharmaceutical composition containing rasagiline mesylate in which the degradation of rasagiline mesylate during storage is sufficiently suppressed. [Means for solving the problem]

[0009] The inventors conducted extensive research to solve the above problems and obtained the following findings. (1) By incorporating the disintegrant carmellose or carmellose calcium into a pharmaceutical composition containing rasagiline mesylate, the generation of rasagiline mesylate-related substances is reduced compared to when the disintegrant low-substituted hydroxypropyl cellulose is incorporated. (2) By combining the lubricant calcium stearate with a pharmaceutical composition containing rasagiline mesylate, the generation of rasagiline mesylate-related substances is reduced compared to when the lubricants magnesium stearate, sodium stearyl fumarate, or stearic acid are combined. (3) When a lubricant is added to a pharmaceutical composition containing rasagiline mesylate together with carmellose or carmellose calcium, the combination of stearic acid and talc results in even less generation of rasagiline mesylate analogs than the combination of calcium stearate.

[0010] This invention was completed based on the above findings and provides the following [1] to [7]. [1] (A) A pharmaceutical composition comprising rasagiline mesylate and carmellose and / or carmellose calcium. [2] The pharmaceutical composition according to [1], further comprising (i) calcium stearate and / or (ii) a combination of stearic acid and talc. [3] A pharmaceutical composition according to [1] or [2], which is in the form of a tablet. [4] The pharmaceutical composition according to any one of [1] to [3], wherein the total content of carmellose and / or carmellose calcium is 0.1 to 40% by mass of the total amount of the composition. [5] The pharmaceutical composition according to [2], comprising calcium stearate, wherein the calcium stearate content is 0.01 to 20% by mass relative to the total amount of the composition. [6] The pharmaceutical composition according to [2], comprising stearic acid and talc, wherein the total content of stearic acid and talc is 0.01 to 20% by mass of the total amount of the composition. [7] A method for suppressing the decomposition of rasagiline mesylate or the generation of related substances due to storage by including carmellose and / or carmellose calcium in a pharmaceutical composition containing rasagiline mesylate. [Effects of the Invention]

[0011] The pharmaceutical composition of the present invention has sufficient suppression of the degradation of rasagiline mesylate. In recent years, there have been concerns that rasagiline mesylate may degrade during normal distribution and storage due to the extreme heat, but because the degradation of rasagiline mesylate is suppressed in the pharmaceutical composition of the present invention, it can be distributed and stored under normal conditions. [Modes for carrying out the invention]

[0012] The present invention will be described in detail below. The pharmaceutical composition of the present invention is a composition comprising rasagiline mesylate and carmellose and / or carmellose calcium.

[0013] The concentration of lasagiline mesylate can be 0.05% by mass or more, 0.1% by mass or more, or 0.4% by mass or more, and can be 10% by mass or less, 5% by mass or less, or 2.6% by mass or less, based on the total amount of the pharmaceutical composition.

[0014] Examples of the particle size distribution of lasagiline mesylate include a distribution in which particles of 6 μm or less are 10% by volume or more of the total amount, a distribution in which particles of 250 μm or more are 10% by volume or more of the total amount, a distribution in which the total of particles of 6 μm or less and particles of 250 μm or more is 10% by volume or more of the total amount, or a distribution in which particles exceeding 6 μm and less than 250 μm exceed 90% by volume of the total amount. The particle size distribution is a value measured by the laser diffraction scattering method.

[0015] The total content of carmellose and / or calcium carmellose can be 0.1% by mass or more, 1% by mass or more, or 2% by mass or more, and can be 40% by mass or less, 30% by mass or less, 20% by mass or less, or 10% by mass or less, based on the total amount of the composition. Within this range, the storage stability of lasagiline mesylate can be sufficiently improved, and the decrease in hardness of the pharmaceutical composition due to moisture absorption and the decomposition of components can be suppressed.

[0016] The pharmaceutical composition of the present invention can further contain (i) calcium stearate and / or (ii) a combination of stearic acid and talc, whereby the storage stability of lasagiline mesylate is further improved. The content of calcium stearate can be 0.01% by mass or more, 0.1% by mass or more, or 0.5% by mass or more, and can be 20% by mass or less, 10% by mass or less, or 5% by mass or less, based on the total amount of the composition. Within this range, the storage stability of lasagiline mesylate can be sufficiently improved, and the decrease in hardness of the pharmaceutical composition, the delay in disintegration, and the delay in elution of components can be suppressed.

[0017] The total content of stearic acid and talc can be 0.01% by mass or more, 0.1% by mass or more, or 0.5% by mass or more, and can be 20% by mass or less, 10% by mass or less, or 5% by mass or less, based on the total amount of the composition. Within this range, the storage stability of lasagiline mesylate can be sufficiently improved, and also the decrease in hardness, delay in disintegration, and delay in elution of components can be suppressed.

[0018] Examples of the dosage form of the pharmaceutical composition of the present invention include solid preparations such as tablets, powders, granules, fine granules, capsules (hard capsules, soft capsules), dry syrups, films, lozenges, chewing gum preparations, etc. Among them, tablets are preferred.

[0019] In addition to carmellose, calcium carmellose, calcium stearate, stearic acid, and talc, the pharmaceutical composition of the present invention can contain various additives added to the pharmaceutical composition. Examples of such additives include excipients, binders, disintegrants, lubricants, fluidizing agents, glazing agents, stabilizers, antioxidants, emulsifiers, surfactants, solubilizers, suspending agents, dispersants, buffers, pH adjusters, thickeners, adsorbents, coloring agents, flavoring agents, sweetening agents, fragrances, preservatives or antiseptics, foaming agents, defoaming agents, coating agents, plasticizers, etc. One or more additives can be used.

[0020] Excipients include erythritol, lactose / crystalline cellulose spherical granules, sugar powder, gum arabic, gum arabic powder, pregelatinized starch, partially pregelatinized starch, starch (wheat starch, rice starch, potato starch, corn starch), isomalt monohydrate (ISOMALT), kaolin, reduced palatinose, xylitol, L-glutamine, croscarmellose sodium, crospovidone, silicate-treated crystalline cellulose, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, synthetic hydrotalcite, titanium dioxide, β-cyclodextrin, aluminum hydroxide gel, refined sucrose, refined sucrose spherical granules, gelatin, D-sorbitol, talc, medium-chain triglyceride. Examples include precipitated calcium carbonate, low-substituted hydroxypropyl cellulose, sodium starch glycolate (sodium carboxymethyl starch), trehalose hydrate, lactose hydrate, sucrose, sucrose / 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, glyceryl monostearate, monocalcium hydrogen phosphate, and calcium hydrogen phosphate hydrate.

[0021] The binders include cellulosic binders (ethylcellulose, methylcellulose, hydroxypropylcellulose, hypromellose, carboxymethylethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylethylcellulose, calcium carboxymethylethylcellulose, hydroxyethylcellulose, hypromellose acetate succinate, hypromellose phthalate), gum arabic, gum arabic powder, pregelatinized starch, partially pregelatinized starch, starch (wheat starch, rice starch, corn starch, potato starch), hydroxypropyl starch, sodium alginate, gelatin, low-substituted hydroxypropylcellulose, dextrin, sodium starch glycolate (sodium carboxymethyl starch), pullulan, macrogol (macrogol Examples include polyvinyl alcohol (400, macrogol 4000, macrogol 6000), ethyl acrylate / methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer (such as aminoalkyl methacrylate copolymer E), ammoniaalkyl 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, and methacrylate copolymer (dried methacrylate copolymer LD, methacrylate copolymer L, methacrylate copolymer LD, methacrylate copolymer S).

[0022] Other disintegrants besides carmellose and carmellose calcium include starch (wheat starch, rice starch, potato starch, corn starch), sodium starch glycolate (carboxymethyl starch sodium), hydroxypropyl starch, hydroxypropyl cellulose, partially pregelatinized starch, croscarmellose sodium, crospovidone, light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, magnesium aluminometasilicate, calcium silicate, and sodium lauryl sulfate.

[0023] Other lubricants besides calcium stearate, stearic acid, and talc include glyceryl monostearate, dimethylpolysiloxane (for oral use), sucrose fatty acid esters, stearates (magnesium stearate, sodium stearyl fumarate), and dl-leucine.

[0024] Other fluidizing agents besides talc include calcium silicate, light anhydrous silicic acid, hydrated silicon dioxide, synthetic aluminum silicate, and magnesium aluminometasilicate.

[0025] Examples of polishing agents include carnauba wax, refined paraffin-carnauba wax mixture, bleached beeswax, and refined shellac.

[0026] 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 aluminometasilicate, glyceryl monostearate, sucrose fatty acid ester, stearic acid, sodium lauryl sulfate, macrogol (macrogol 400, macrogol 4000, etc.), carboxyvinyl polymer, and polyvinyl alcohol. Examples include ru (partially saponified), polyoxyethylene hydrogenated castor oil (N), sodium lauryl sulfate, L-aspartic acid, sodium L-aspartate hydrate, DL-alanine, L-alanine, L-arginine, sodium chloride, dried aluminum hydroxide gel, xanthan gum, glycine, acetic acid, sodium acetate hydrate, sodium hydroxide, sodium bicarbonate, tocopherol, lactic acid, concentrated glycerin, butylhydroxyanisole, fumaric acid, propylene glycol, propyl gallate, polysorbate 80, and anhydrous sodium monohydrogen phosphate.

[0027] Examples of antioxidants include anhydrous citric acid, citric acid hydrate, soy lecithin, dibutylhydroxytoluene, tocopherol, and propyl gallate.

[0028] Examples of emulsifiers include glyceryl monostearate, polyoxyethylene hydrogenated castor oil (N), polysorbate 80, sodium lauryl sulfate, medium-chain triglyceride, soy lecithin, and lauromacrogol.

[0029] Examples of surfactants include glyceryl monostearate, polyoxyethylene hydrogenated castor oil (N), polysorbate 80, sodium lauryl sulfate, lauromacrogol, macrogol (such as macrogol 400), and polyoxyethylene (N) polyoxypropylene (N) glycol.

[0030] Examples of solubilizers include polyoxyethylene hydrogenated castor oil (N), polysorbate 80, lauromacrogol, polyoxyethylene (N) polyoxypropylene (N) glycol, sodium lauryl sulfate, medium-chain triglyceride, soy 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.

[0031] Examples of suspending agents include polyoxyethylene hydrogenated castor oil (N), polysorbate 80, soy lecithin, sucrose fatty acid ester, macrogol (macrogol 4000, macrogol 6000, etc.), sodium hydroxide, hydroxypropyl cellulose, glycerin, D-sorbitol, magnesium aluminometasilicate, carboxyvinyl polymer, dried aluminum hydroxide gel, xanthan gum, butylhydroxyanisole, propylene glycol, crystalline cellulose, gum arabic, gum arabic powder, hypromellose, agar powder, povidone, methylcellulose, kaolin, carrageenan, sodium carmellose, glycerin fatty acid ester, and magnesium aluminum silicate.

[0032] Examples of dispersants include propylene glycol alginate, ethanol, carboxymethylcellulose sodium, citric acid hydrate, sodium citrate hydrate, glycerin, glycerin fatty acid ester, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, crystalline cellulose / carboxymethylcellulose sodium, titanium dioxide, sucrose fatty acid ester, stearic acid, magnesium stearate, oleic acid, sorbitan fatty acid ester, 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.

[0033] 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 monohydrogen phosphate, L-glutamic acid, and dilute hydrochloric acid.

[0034] 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 monohydrogen phosphate, dilute hydrochloric acid, sodium hydroxide, meglumine, succinic acid, and ammonia water.

[0035] 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.

[0036] Examples of adsorbents include magnesium aluminometasilicate, kaolin, light anhydrous silicic acid, synthetic aluminum silicate, magnesium silicate, and precipitated calcium carbonate.

[0037] Examples of coloring agents include titanium dioxide, indigo carmine, yellow iron(III) oxide, carmine, black iron oxide, iron(III) oxide, synthetic food colorings (such as Blue No. 1, Blue No. 2 aluminum lake, Yellow No. 4, Yellow No. 4 aluminum lake, Yellow No. 5, Red No. 2, Red No. 3, Red No. 102, etc.), and natural food colorings.

[0038] Examples of flavoring agents include erythritol, xylitol, refined sucrose, D-sorbitol, lactose monohydrate, sucrose, glucose, D-mannitol, aspartame, cocoa powder, reduced maltose syrup, reduced starch syrup, licorice, licorice extract, citric acid monohydrate, sodium citrate monohydrate, L-glutamic acid, succinic acid, saccharin, sodium saccharin monohydrate, tartaric acid, sucralose, refined stevia extract, peppermint oil, anhydrous citric acid, l-menthol, and DL-malic acid.

[0039] Examples of sweeteners include xylitol, refined sucrose, D-sorbitol, lactose monohydrate, sucrose, glucose, D-mannitol, aspartame, reduced maltose syrup, licorice, licorice extract, saccharin, sodium saccharin monohydrate, sucralose, refined stevia extract, maltitol, acesulfame potassium, and thaumatin.

[0040] Examples of fragrances include peppermint oil, l-menthol, and vanillin.

[0041] Examples of preservatives or antimicrobial agents include citric acid hydrate, sodium benzoate, sodium edetate hydrate, dibutylhydroxytoluene, and parahydroxybenzoic acid esters (such as isobutyl parahydroxybenzoate, isopropyl parahydroxybenzoate, ethyl parahydroxybenzoate, butyl parahydroxybenzoate, propyl parahydroxybenzoate, and methyl parahydroxybenzoate).

[0042] Examples of foaming agents include bicarbonates (such as sodium bicarbonate and potassium bicarbonate) and carbonates (such as magnesium carbonate and calcium carbonate).

[0043] Examples of coating agents include water-soluble coating agents such as cellulose-based coating agents like methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose), hydroxypropylcellulose phthalate, carboxymethylethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hypromellose phthalate, hypromellose succinate acetate, cellulose acetate, and cellulose phthalate acetate; vinyl polymers such as carboxyvinyl polymer, polyvinyl alcohol, povidone, copolividone, and polyvinyl alcohol-polyethylene glycol copolymer; polyoxyethylene-polyoxypropylene glycol; polyethylene glycol (macrogol); methacrylate polymers or methacrylic acid polymers. Examples of methacrylate polymers or methacrylic acid polymers include Rhehm's aminoalkyl methacrylate copolymer E (Eudragit® 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.).

[0044] Examples of plasticizers include polyethylene glycol, propylene glycol, glycerin, glycerin fatty acid esters such as triacetin (glycerin triacetic acid), liquid paraffin, sorbitan monolaurate, monostearin, triethyl citrate, tributyl citrate, diethyl phthalate, dibutyl phthalate, diethyl sebacate, dibutyl sebacate, poloxamer, and polyoxyethylene hydrogenated castor oil.

[0045] The pharmaceutical composition of the present invention may be formulated according to conventional methods. When the pharmaceutical composition of the present invention is in the form of tablets, it can be manufactured by mixing rasagiline mesylate with additives, granulating the mixture, and then compressing it into tablets either as is or after further mixing with additives, or by mixing all the components and then compressing them into tablets. In the former method, carmellose and / or carmellose calcium may be included in the granules, and calcium stearate, stearic acid, and talc may be included in the additives mixed with the granules. Therefore, examples of tablets include those uniformly containing rasagiline mesylate, carmellose and / or carmellose calcium, and optionally calcium stearate and / or stearic acid and talc; those containing rasagiline mesylate and carmellose and / or carmellose calcium as a granular portion; and those containing rasagiline mesylate and carmellose and / or carmellose calcium as a granular portion, with calcium stearate and / or stearic acid and talc as a separate portion from the granules.

[0046] The present invention provides a method for suppressing the decomposition of rasagiline mesylate or the generation of related substances during storage by including carmellose and / or carmellose calcium in a pharmaceutical composition containing rasagiline mesylate. In this method, the pharmaceutical composition containing rasagiline mesylate may further include (i) calcium stearate and / or (ii) a combination of stearic acid and talc. In this method, the components, composition, properties, and manufacturing method of the pharmaceutical composition are as described for the pharmaceutical composition of the present invention. [Examples]

[0047] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0048] (1) Method for quantifying related substances of rasagiline mesylate Related substances to rasagiline mesylate were quantified by HPLC under the following conditions. Using a standard substance of rasagiline mesylate, peaks other than those for the solvent, additive, and rasagiline were identified as peaks for related substances. (HPLC conditions) Column: XBridge C18 (product name) Column temperature: 30℃ Mobile phase A: Dissolve 1.36 g of potassium dihydrogen phosphate in 1000 mL of water and add 1 mL of triethylamine. Add diluted phosphoric acid (1→10) to adjust the pH to 6.5. Mobile phase B: Acetonitrile Mobile phase flow rate: 1.0 mL per minute Detector: UV absorbance spectrophotometer (measurement wavelength: 210 nm) Time program [Table 1] The total percentage of related substances in the sample was calculated according to the following formula. The concentration of rasagiline mesylate in the standard solution was set to 1% relative to the sample solution. Individual related substance (%) = Individual peak area / Peak area of ​​standard solution Total amount of related substances (%) = Sum of peak areas of individual related substances / Peak area of ​​standard solution

[0049] (2) Manufacturing of tablets In each of the following examples, rasagiline mesylate was used, in which particles smaller than 6 μm accounted for 10% or more of the total volume. Example 1 2.34 g of rasagiline mesylate, 289.98 g of D-mannitol, and 15.75 g of carmellose were placed in a fluid-bed granulator and dried while spraying 78.15 g of a 4.0% polyvinyl alcohol aqueous solution. 228.23 g of the granules that passed through the 32 Mesh were mixed with 2.77 g of calcium stearate and compressed in a rotary tablet press to obtain tablets with the composition shown in Table 2. Example 2 Tablets with the composition shown in Table 2 were manufactured in the same manner as in Example 1, except that the same amount of carmellose calcium was used instead of carmellose. Comparative Example 1 In Example 1, low-substituted hydroxypropyl cellulose was used instead of carmellose to produce tablets with the composition shown in Table 2.

[0050] [Table 2]

[0051] Comparative Example 2 Rasagiline mesylate 1.87 g, D-mannitol 191.09 g, light anhydrous silicic acid 1.44 g, corn starch 24.00 g, partially pregelatinized starch 24.00 g, talc 4.80 g, and calcium stearate 4.80 g were mixed and compressed in a rotary tablet press to obtain tablets with the composition shown in Table 3. Comparative Example 3 In Comparative Example 2, the same amount of magnesium stearate was used instead of calcium stearate, and tablets with the composition shown in Table 3 were manufactured in the same manner as in Comparative Example 2.

[0052] [Table 3]

[0053] Example 3 2.34 g of rasagiline mesylate, 289.98 g of D-mannitol, and 15.75 g of carmellose were placed in a fluid-bed granulator and dried while spraying 78.15 g of a 4.0% polyvinyl alcohol aqueous solution. 228.23 g of the granules that passed through the 32 Mesh were mixed with 2.77 g of calcium stearate and compressed in a rotary tablet press to obtain tablets with the composition shown in Table 4. Example 4 In Example 3, stearic acid and talc were used instead of calcium stearate to produce tablets with the composition shown in Table 4. Comparative Example 4 In Example 3, low-substituted hydroxypropyl cellulose was used instead of carmellose to produce tablets with the composition shown in Table 4. Comparative Example 5 In Example 3, low-substituted hydroxypropyl cellulose was used instead of carmellose, and stearic acid and talc were used instead of calcium stearate to produce tablets with the composition shown in Table 4.

[0054] [Table 4]

[0055] (3) Stability test Stability of rasagiline mesylate in tablets The tablets from Examples 1-4 and Comparative Examples 1-5 were sealed in aluminum blister packs and left to stand for 4 weeks at 55°C and 75% RH. Related substances were then quantified. The results are shown in Tables 2-4. As shown in Table 2, when carmellose or carmellose calcium was used as a disintegrant, the amount of related substances was lower than when low-substituted hydroxypropyl cellulose was used. Furthermore, as shown in Table 3, when calcium stearate was used as a lubricant, the amount of related substances was lower than when magnesium stearate was used. Furthermore, as shown in Table 4, the amount of related substances was reduced by incorporating carmellose or carmellose calcium (comparison between Example 3 and Comparative Example 4, and comparison between Example 4 and Comparative Example 5). In addition, the amount of related substances was reduced when stearic acid and talc were incorporated compared to when calcium stearate was incorporated as a lubricant (comparison between Example 3 and Example 4, and comparison between Comparative Example 4 and Comparative Example 5).

[0056] Stability of rasagiline mesylate in the mixture Rasagiline mesylate and the lubricants listed in Table 5 were mixed in a mass ratio of 1:5 and allowed to stand under open conditions at 55°C and 75% RH for 4 weeks. The related substances were then quantified. The results are shown in Table 5. [Table 5] When mixed with calcium stearate, the amount of related substances produced was less compared to when mixed with magnesium stearate, sodium stearyl fumarate, or stearic acid. [Industrial applicability]

[0057] Because the breakdown of rasagiline mesylate in the pharmaceutical composition of the present invention is suppressed, it can be distributed and stored under normal management conditions even during the extreme heat of recent years, thus having high commercial value.

Claims

1. (A) A pharmaceutical composition comprising rasagiline mesylate and carmellose and / or carmellose calcium.

2. Furthermore, the pharmaceutical composition according to claim 1, comprising (i) calcium stearate and / or (ii) a combination of stearic acid and talc.

3. A pharmaceutical composition according to claim 1 or 2, which is in the form of a tablet.

4. The pharmaceutical composition according to claim 1 or 2, wherein the total content of carmellose and / or carmellose calcium is 0.1 to 40% by mass of the total amount of the composition.

5. The pharmaceutical composition according to claim 2, comprising calcium stearate, wherein the calcium stearate content is 0.01 to 20% by mass of the total amount of the composition.

6. The pharmaceutical composition according to claim 2, comprising stearic acid and talc, wherein the total content of stearic acid and talc is 0.01 to 20% by mass of the total amount of the composition.

7. A method for suppressing the decomposition of rasagiline mesylate or the generation of related substances during storage by including carmellose and / or carmellose calcium in a pharmaceutical composition containing rasagiline mesylate.

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