Rasagiline mesylate-containing preparation

Abstract

To provide a rasagiline mesylate-containing preparation that suppresses formation of related substances derived from rasagiline.SOLUTION: In one embodiment of the invention, there is provided a rasagiline mesylate-containing preparation comprising rasagiline mesylate and propyl gallate, wherein the amount of propyl gallate per 1 mg of rasagiline may be more than 2 mg and 5 mg or less.SELECTED DRAWING: None

Description

[Technical Field]

[0001] One embodiment of the present invention relates to a preparation containing rasagiline mesylate in which the production of related substances is suppressed. [Background technology]

[0002] Rasagiline (R(+)-N-propargyl-1-aminoindan) is a selective inhibitor of MAO-B and is used to treat Parkinson's disease (e.g., Patent Document 1). Rasagiline mesylate is contained in the formulation.

[0003] Non-Patent Document 1 describes that the amount of related substances increases when rasagiline mesylate-containing preparations commercially available at the time of filing of this application are stored at 40°C, 75% relative humidity (75% RH), and under light-protected conditions. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Patent No. 5738509 [Patent Document 2] Patent No. 5774495 [Non-patent literature]

[0005] [Non-Patent Document 1] Azilect® Tablets Drug Interview Form, September 2022 Revised (9th Edition) Summary of the Invention [Problem to be solved by the invention]

[0006] An object of one embodiment of the present invention is to provide a preparation containing rasagiline mesylate that inhibits the production of analogues derived from rasagiline. [Means for solving the problem]

[0007] A rasagiline mesylate-containing formulation according to one embodiment of the present invention contains rasagiline mesylate and propyl gallate.

[0008] It may contain more than 2 mg but not more than 5 mg of propyl gallate per 1 mg of rasagiline. [Effects of the Invention]

[0009] According to one embodiment of the present invention, there is provided a preparation containing rasagiline mesylate in which the production of analogues derived from rasagiline is suppressed. DETAILED DESCRIPTION OF THE INVENTION

[0010] The rasagiline mesylate-containing formulation of the present invention will be described below with reference to the drawings. Note that the rasagiline mesylate-containing formulation of the present invention should not be construed as being limited to the description of the following embodiments and examples.

[0011] As a result of studies by the present inventors, it is presumed that 1-aminoindan, a substance related to rasagiline, is generated by thermal decomposition of rasagiline in formulations containing rasagiline mesylate. The addition of antioxidants is generally known as a means of inhibiting the oxidative decomposition of active pharmaceutical ingredients. For example, Patent Document 2 describes the possibility of adding several antioxidants. However, it cannot be generally assumed that the addition of antioxidants can inhibit the generation of 1-aminoindan, which is presumed to be generated by thermal decomposition of rasagiline. In fact, further studies by the present inventors revealed that not all antioxidants can inhibit the generation of related substances, and that some antioxidants actually increase the amount of related substances generated.

[0012] The rasagiline mesylate-containing formulation according to this embodiment contains rasagiline mesylate and propyl gallate. Studies by the present inventors have revealed that the production of rasagiline-derived analogues is significantly suppressed in rasagiline mesylate-containing formulations containing propyl gallate. Propyl gallate is an additive not described in Patent Document 2, and therefore cannot be easily selected from the description in Patent Document 2.

[0013] In this embodiment, the effect of inhibiting the production of rasagiline-derived analogs in a rasagiline mesylate-containing formulation shows a positive correlation with the amount of propyl gallate added. In one embodiment, the rasagiline mesylate-containing formulation preferably contains more than 2 mg of propyl gallate per 1 mg of rasagiline. In another embodiment, the rasagiline mesylate-containing formulation may contain 5 mg or less of propyl gallate per 1 mg of rasagiline. Since the maximum daily dose of propyl gallate is 5 mg, the amount of propyl gallate contained in the rasagiline mesylate-containing formulation of this embodiment is limited to 5 mg per 1 mg of rasagiline. For example, the content of propyl gallate in the rasagiline mesylate-containing formulation may be 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, or 5.0 mg per 1 mg of rasagiline.

[0014] Examples of excipients that can be used in the rasagiline mesylate-containing formulation of this embodiment include, but are not limited to, one or more selected from the group consisting of lactose, gelatin, agar, starch, sucrose, glucose, methylcellulose, mannitol, sorbitol, and crystalline cellulose.

[0015] Examples of binders that can be used in the rasagiline mesylate-containing formulation of this embodiment include, but are not limited to, one or more selected from the group consisting of starch, gelatin, glucose or β-lactose, corn starch, gum arabic, gum tragacanth, povidone, carboxymethylcellulose, polyethylene glycol, hydroxypropyl cellulose, and wax.

[0016] Examples of disintegrants that can be used in the rasagiline mesylate-containing formulation of this embodiment include, but are not limited to, one or more selected from the group consisting of starch (corn starch, partially pregelatinized starch, or pregelatinized starch), low-substituted hydroxypropyl cellulose, methylcellulose, agar, bentonite, and xanthan gum.

[0017] Lubricants that can be used in the rasagiline mesylate-containing formulation of this embodiment include, but are not limited to, one or more selected from the group consisting of stearic acid, hydrogenated oil, sucrose fatty acid ester, light anhydrous silicic acid, and talc. In one embodiment, in order to obtain sufficient lubricating properties and fluidity, the rasagiline mesylate-containing formulation preferably contains light anhydrous silicic acid and / or talc in addition to the above-mentioned oily additives.

[0018] The content of rasagiline mesylate in the rasagiline mesylate-containing formulation according to this embodiment can be set arbitrarily within a range that provides a therapeutic effect. For example, the rasagiline mesylate-containing formulation may contain rasagiline mesylate so that the content of rasagiline per tablet is 0.5 mg or 1 mg, but is not limited thereto.

[0019] [Manufacturing method of rasagiline mesylate-containing preparations] The rasagiline mesylate-containing formulation according to this embodiment can be produced by a known method. For example, the rasagiline mesylate-containing formulation may be produced by granulating rasagiline mesylate, propyl gallate, and one or more of the additives (fillers, binders, and disintegrants) by a wet granulation method (e.g., a stirring and kneading method), mixing the resulting granules with one or more of the additives (fillers and lubricants), and tableting the mixture, but is not limited thereto.

[0020] [Stability evaluation] In the present specification, the stability of rasagiline in a preparation containing rasagiline mesylate can be evaluated by measuring the amount of related substances using high performance liquid chromatography (HPLC). [Example]

[0021] [Comparative Example 1] A rasagiline mesylate-containing formulation not containing additives commonly used as antioxidants was prepared as Comparative Example 1. Specifically, 1.56 g of rasagiline mesylate, 147.8 g of D-mannitol (Mannit-P, Mitsubishi Corporation Life Sciences Co., Ltd.), 20.0 g of corn starch (XX16W, Nippon Shokuhin Kako Co., Ltd.), 20.0 g of partially pregelatinized starch (PCS, Asahi Kasei Corporation), and 11.6 g of pregelatinized starch (Amycol® C, Nippon Starch Chemical Co., Ltd.) were placed in a mixing and kneading apparatus (EarthTechnica Corporation, model: HSM-2L) and mixed, followed by adding purified water and mixing. The mixture was then dried in a fluidized bed granulator (Powrex Corporation, model MP-01). The resulting granules were sized using a granulator (Dalton Corporation, model Power Mill), and then homogenously mixed with 1.0 g of light anhydrous silicic acid (Adsolider® 101, Freund Corporation), 4.0 g of stearic acid (Japanese Pharmacopoeia Stearic Acid NAA®-180P-1, NOF Corporation), and 4.0 g of talc (Fuji Talc Industries Co., Ltd.) to obtain a pre-tabletting powder. The pre-tabletting powder was compressed into tablets (VELA5, Kikusui Seisakusho Co., Ltd.) to yield a rasagiline mesylate-containing formulation of Comparative Example 1, each tablet containing 210 mg of rasagiline.

[0022] [Example 1] A rasagiline mesylate-containing formulation containing propyl gallate as an antioxidant was prepared in Example 1. Specifically, 1.56 g of rasagiline mesylate, 142.8 g of D-mannitol (Mannit-P, Mitsubishi Corporation Life Sciences Co., Ltd.), 20.0 g of corn starch (XX16W, Nippon Shokuhin Kako Co., Ltd.), 20.0 g of partially pregelatinized starch (PCS, Asahi Kasei Corporation), 11.6 g of pregelatinized starch (Amycol® C, Nippon Starch Chemical Co., Ltd.), and 5.0 g of propyl gallate were placed in a mixing and kneading apparatus (EarthTechnica Corporation, model: HSM-2L) and mixed, followed by adding purified water and mixing. The mixture was then dried in a fluidized bed granulator (Powrex Corporation, model MP-01). The resulting granules were sized using a granulator (Dalton Corporation, model Power Mill) and homogenized with 1.0 g of light anhydrous silicic acid (Adsolider® 101, Freund Corporation), 4.0 g of stearic acid (Japanese Pharmacopoeia Stearic Acid NAA®-180P-1, NOF Corporation), and 4.0 g of talc (Fuji Talc Industries Co., Ltd.) to obtain a powder before tableting. The powder before tableting was compressed into tablets of 210 mg each using a tablet press (VELA5, Kikusui Seisakusho Co., Ltd.) to produce the rasagiline mesylate-containing formulation of Example 1. The rasagiline mesylate-containing formulation of Example 1 contained 1 mg of rasagiline and 5 mg of propyl gallate per tablet.

[0023] The rasagiline mesylate-containing formulations of Comparative Example 1 and Example 1 were sealed in a hard vinyl chloride sheet (SUMILITE (registered trademark) VSS-F120, Sumitomo Bakelite Co., Ltd.) and stored for 3 months at 40°C and 75% RH. The rasagiline mesylate-containing formulations of Comparative Example 1 and Example 1 were sealed in an ultra-high moisture-proof sheet (SUMILITE (registered trademark) FCL-1135, Sumitomo Bakelite Co., Ltd.) and stored for 3 months at 40°C and 75% RH. The rasagiline mesylate-containing formulations of Comparative Example 1 and Example 1 were sealed in a hard vinyl chloride sheet (SUMILITE (registered trademark) VSS-F120, Sumitomo Bakelite Co., Ltd.), further sealed in an aluminum pillow, and stored for 1 week at 60°C and 60% RH.

[0024] [Stability evaluation] The amount of related substances (%) was measured for the rasagiline mesylate-containing formulations of Comparative Example 1 and Example 1 immediately after production (initial) and after storage. Approximately 20 ml of a phosphate aqueous solution:methanol mixture (4:1) was added to the rasagiline mesylate-containing formulation and stirred. This solution was filtered through a membrane filter with a pore size of 0.45 μm or less. At least 2 ml of the first filtrate was removed, and the next filtrate was used as the sample solution. The amount of related substances was measured by HPLC using an accurate 50 μl sample of the sample solution. Using the area percentage method, the sum of the peak areas of each component of rasagiline and rasagiline-derived related substances obtained on the chromatogram was set to 100, and the amount of rasagiline-derived related substances (%) was calculated from the ratio of the peak areas. The calculated amounts of related substances are shown in Table 1.

[0025] [Table 1]

[0026] The results in Table 1 demonstrate that, under all storage conditions, the addition of propyl gallate, a known antioxidant, can suppress the formation of 1-aminoindan, which is presumed to be produced by thermal decomposition of rasagiline. It was also revealed that the addition of propyl gallate also suppresses the overall formation of rasagiline-derived analogues.

[0027] Comparative Example 2 In Comparative Example 2, a rasagiline mesylate-containing formulation was produced in the same manner as in Example 1, except that propyl gallate was replaced with 4.0 g of dibutylhydroxytoluene (BHT) used as an antioxidant, and the amount of D-mannitol added was changed accordingly. The rasagiline mesylate-containing formulation of Comparative Example 2 contained 4 mg of BHT so as to be equimolar to propyl gallate.

[0028] Comparative Example 3 In Comparative Example 3, a rasagiline mesylate-containing formulation was produced in the same manner as in Example 1, except that 5.0 g of ascorbic acid used as an antioxidant was used instead of propyl gallate. The rasagiline mesylate-containing formulation of Comparative Example 3 contained 5 mg of ascorbic acid, which was equimolar to propyl gallate.

[0029] Comparative Example 4 In Comparative Example 4, a rasagiline mesylate-containing formulation was produced in the same manner as in Example 1, except that propyl gallate was replaced with 2.0 g of tocopherol used as an antioxidant and the amount of D-mannitol added was changed accordingly. The rasagiline mesylate-containing formulation of Comparative Example 4 contained 2 mg of tocopherol, equivalent to the molar amount of propyl gallate.

[0030] The rasagiline mesylate-containing preparations of Comparative Examples 2 to 4 were sealed in a hard vinyl chloride sheet (SUMILITE (registered trademark) VSS-F120, Sumitomo Bakelite Co., Ltd.) and stored for 3 months at 40°C and 75% RH. The rasagiline mesylate-containing preparations of Comparative Example 1 and Example 1 were sealed in an ultra-high moisture-proof sheet (SUMILITE (registered trademark) FCL-1135, Sumitomo Bakelite Co., Ltd.) and stored for 3 months at 40°C and 75% RH.

[0031] [Stability evaluation] The amount (%) of related substances was measured by the method described above for the rasagiline mesylate-containing preparations of Comparative Examples 2 to 4 immediately after production (initial) and after storage. The calculated amounts of related substances are shown in Table 2. The results of Comparative Example 1 and Example 1 described above are also shown in Table 2.

[0032] [Table 2]

[0033] The results in Table 2 show that, compared to the rasagiline mesylate-containing formulation of Comparative Example 1 containing no antioxidant, the rasagiline mesylate-containing formulations containing BHT (Comparative Example 2), ascorbic acid (Comparative Example 3), and tocopherol (Comparative Example 4) used as antioxidants were unable to inhibit the production of rasagiline-derived analogs, including 1-aminoindan, and the addition of ascorbic acid (Comparative Example 3) or tocopherol (Comparative Example 4) actually increased the total amount of analogs produced compared to Comparative Example 1. These results demonstrate that propyl gallate can specifically inhibit the production of rasagiline-derived analogs.

[0034] [Example 2] The relationship between the propyl gallate content and the inhibitory effect on the production of rasagiline-derived analogues was investigated. Rasagiline mesylate-containing formulations were produced in the same manner as in Example 1, except that the amount of propyl gallate added was changed so that the propyl gallate content was 1 mg, 2 mg, 3 mg, or 4 mg per tablet, and the amount of D-mannitol added was changed depending on the amount of propyl gallate added. Each rasagiline mesylate-containing formulation with a different propyl gallate content was sealed in a hard polyvinyl chloride sheet (Sumilite (registered trademark) VSS-F120, Sumitomo Bakelite Co., Ltd.) and stored at 40°C and 75% RH for 3 months.

[0035] [Stability evaluation] The amount (%) of related substances in the rasagiline mesylate-containing preparations after storage was measured using the method described above. The calculated amounts of related substances are shown in Table 3. The results of Example 1 (propyl gallate content: 5 mg) are also shown in Table 3.

[0036] [Table 3]

[0037] The results in Table 3 demonstrate that in rasagiline mesylate-containing preparations containing more than 2 mg of propyl gallate, the production of rasagiline-derived analogues is inhibited, and that this effect is positively correlated with the propyl gallate content.

Claims

1. A rasagiline mesylate-containing formulation comprising rasagiline mesylate and propyl gallate.

2. 2. The rasagiline mesylate-containing formulation according to claim 1, comprising more than 2 mg and not more than 5 mg of propyl gallate per 1 mg of rasagiline.

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