Rasagiline mesilate-containing formulation

Abstract

To provide a rasagiline mesilate-containing formulation that enables suppression of delayed dissolution of rasagiline.SOLUTION: According to one embodiment of the present invention, a rasagiline mesilate-containing formulation contains rasagiline mesilate and a pharmaceutically acceptable lubricant having a stearic acid content of 60.0% or more. The rasagiline mesilate-containing formulation may contain, as the lubricant, at least one lubricant selected from the group consisting of stearic acid 70 and stearic acid 95.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] One embodiment of the present invention relates to a rasagiline mesylate-containing preparation in which delay in the dissolution of rasagiline 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 dissolution rate of rasagiline mesylate-containing preparations commercially available at the time of filing the present application decreases over time when stored at 40°C, 75% relative humidity (75% RH) and under light-protected conditions.

[0004] In order to improve the disintegration property of a rasagiline-containing preparation, for example, Patent Document 2 describes a rasagiline-containing preparation containing the active ingredient rasagiline or a salt thereof, and one or more lubricants selected from sodium stearyl fumarate and magnesium stearate. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Patent No. 5738509 [Patent Document 2] Japanese Patent Application Publication No. 2024-037149 [Non-patent literature]

[0006] [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]

[0007] An object of one embodiment of the present invention is to provide a rasagiline mesylate-containing preparation in which delay in the dissolution of rasagiline is suppressed. [Means for solving the problem]

[0008] A rasagiline mesylate-containing formulation according to one embodiment of the present invention comprises rasagiline mesylate and a pharmaceutically acceptable lubricant having a stearic acid content of 60.0% or more.

[0009] The lubricant may include one or more lubricants selected from the group consisting of 70 stearic acid and 95 stearic acid. [Effects of the Invention]

[0010] According to one embodiment of the present invention, there is provided a rasagiline mesylate-containing preparation in which delay in the dissolution of rasagiline is suppressed. [Brief explanation of the drawings]

[0011] [Figure 1] FIG. 1 is a graph showing the dissolution rate of a rasagiline mesylate-containing preparation of Comparative Example 1. [Figure 2] FIG. 1 is a graph showing the dissolution rate of the rasagiline mesylate-containing preparation of Example 1. [Figure 3] FIG. 1 is a graph showing the dissolution rate of the rasagiline mesylate-containing preparation of Example 2. [Figure 4] FIG. 1 shows the dissolution rate of the rasagiline mesylate-containing preparation of Comparative Example 2. [Figure 5] FIG. 1 shows the dissolution rate of the rasagiline mesylate-containing preparation of Comparative Example 3. DETAILED DESCRIPTION OF THE INVENTION

[0012] The rasagiline mesylate-containing formulation of the present invention will be described below with reference to the drawings. It should be noted that the rasagiline mesylate-containing formulation of the present invention should not be construed as being limited to the following embodiments and examples. In the drawings referred to in the present embodiments and examples described below, the same parts or parts having similar functions are designated by the same reference numerals, and repeated explanations thereof will be omitted.

[0013] The rasagiline mesylate-containing formulation of this embodiment contains rasagiline mesylate and a pharmaceutically acceptable lubricant having a stearic acid content of 60.0% or more. Examples of pharmaceutically acceptable lubricants having a stearic acid content of 60.0% or more contained in the rasagiline mesylate-containing formulation of this embodiment include stearic acid 70 and stearic acid 95. Note that, in this specification, "stearic acid" does not include salt forms. Specifically, magnesium stearate, calcium stearate, and sodium stearate are not included in the stearic acid lubricant contained in the rasagiline mesylate-containing formulation of this embodiment.

[0014] In this embodiment, the rasagiline mesylate-containing formulation contains stearic acid 70 and / or stearic acid 95 as a lubricant, and the lubricant content is 0.5% by mass or more and 3.0% by mass or less relative to the mass of the rasagiline mesylate-containing formulation. In one embodiment, the rasagiline mesylate-containing formulation contains 2.0% by mass or less of stearic acid 70 or stearic acid 95 as a lubricant relative to the mass of the rasagiline mesylate-containing formulation. The rasagiline mesylate-containing formulation may use stearic acid 70 and stearic acid 95 in combination as lubricants, but the total amount is preferably 2.0% by mass or less relative to the mass of the rasagiline mesylate-containing formulation.

[0015] In order to obtain sufficient lubricity and flowability, in one embodiment, the rasagiline mesylate-containing formulation preferably contains light anhydrous silicic acid and / or talc in addition to stearic acid 70 and / or stearic acid 95. When light anhydrous silicic acid or talc is selected as the lubricant in the rasagiline mesylate-containing formulation of this embodiment, the total content of the lubricant is adjusted to 3.0% by mass or less, preferably 2.5% by mass or less, relative to the mass of the rasagiline mesylate-containing formulation.

[0016] As described in the 18th edition of the Japanese Pharmacopoeia, stearic acid used as an additive in pharmaceuticals is stearic acid (C18H 36 O2:284.48) and palmitic acid (C 16 H 32 O2:256.42). Stearic acid 70 and stearic acid 95 contain the amount of stearic acid and the total amount of stearic acid and palmitic acid shown in Table 1.

[0017] [Table 1] [Table 1]

[0018] As shown in the Examples and Comparative Examples described below, the inventors' investigations have suggested that a lubricant with a low melting point or freezing point affects the dissolution of rasagiline in rasagiline mesylate-containing formulations. For example, when stored under high-temperature and high-humidity conditions such as 60°C and 60% RH or 40°C and 75% RH, a rasagiline mesylate-containing formulation containing a lubricant with a melting point or freezing point of less than 57°C exhibited delayed dissolution of rasagiline. However, further investigations by the inventors have revealed that the rasagiline mesylate-containing formulation according to this embodiment cannot suppress the delay in dissolution simply by containing a lubricant with a melting point or freezing point of 57°C or higher, but that the addition of one or more lubricants selected from the group consisting of stearic acid 70 and stearic acid 95 can suppress the delay in dissolution of rasagiline. Thus, a person skilled in the art would never have predicted from the prior art that a rasagiline mesylate-containing formulation containing one or more lubricants selected from the group consisting of stearic acid 70 and stearic acid 95 would suppress the delay in dissolution of rasagiline.

[0019] Examples of excipients that can be used in 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.

[0020] Examples of binders that can be used in 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 waxes.

[0021] Examples of disintegrants that can be used in 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.

[0022] 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.

[0023] [Manufacturing method of rasagiline mesylate-containing preparations] The rasagiline mesylate-containing formulation of this embodiment can be produced by a known method. For example, the rasagiline mesylate-containing formulation of this embodiment can be produced by granulating rasagiline mesylate and one or more of the additives (fillers, binders, and disintegrants) by a wet granulation method (e.g., fluidized bed granulation or stirring kneading), mixing the resulting granules with one or more of the additives (e.g., fillers) and one or more lubricants selected from the group consisting of stearic acid 70 and stearic acid 95 (light anhydrous silicic acid and / or talc may also be added as needed), and tableting the mixture.

[0024] [Evaluation of dissolution] In this specification, the dissolution property of rasagiline in a preparation containing rasagiline mesylate can be evaluated using dissolution test fluid 1 according to dissolution test method 2 (paddle method) described in the 18th edition of the Japanese Pharmacopoeia. [Example]

[0025] [Comparative Example 1] As Comparative Example 1, a formulation containing rasagiline mesylate was produced using stearic acid 50. Specifically, 1.56 g of rasagiline mesylate, 138.8 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 (registered trademark) C, Nippon Starch Chemical Co., Ltd.) were charged into a mixing and kneading apparatus (HSM-2L, Earth Technica Co., Ltd.) and mixed, and purified water was added and mixed. The mixture was then dried in a fluidized bed granulator (MP-01, Powrex Corporation), and the resulting granules were sized using a granulator (Power Mill, Dalton Corporation). Then, 9.0 g of D-mannitol (Granutol-S, Freund Corporation), 1.0 g of light anhydrous silicic acid (Adsolider® 101, Freund Corporation), 4.0 g of stearic acid 50 (Kolliwax® S Fine, BASF Japan Ltd.), and 4.0 g of talc (Fuji Talc Co., Ltd.) were homogeneously mixed to obtain a pre-tabletting powder. The pre-tabletting powder was compressed into tablets weighing 210 mg each using a tablet press (VELA5, Kikusui Seisakusho Co., Ltd.), producing the rasagiline mesylate-containing formulation of Comparative Example 1.

[0026] The rasagiline mesylate-containing formulation of Comparative Example 1 was sealed in an ultra-high moisture-proof sheet (Sumilite® FCL-1135, Sumitomo Bakelite Co., Ltd.) and stored for 1 week under conditions of 60°C and 60% RH. A dissolution test was conducted on the rasagiline mesylate-containing formulation of Comparative Example 1 immediately after production (initial) and after storage using a dissolution tester (Toyama Sangyo Co., Ltd.) in accordance with Dissolution Test Method 2 (paddle method, 50 rpm) of the Japanese Pharmacopoeia, 18th Edition, using 900 ml of Dissolution Test Fluid 1 (pH 1.2) of the Japanese Pharmacopoeia, 18th Edition. The dissolution test was conducted twice using one tablet of the rasagiline mesylate-containing formulation of Comparative Example 1 as a sample, and the average value was used as the dissolution rate. The dissolution rates of the rasagiline mesylate-containing formulation of Comparative Example 1 immediately after production (initial) and after storage are shown in Figure 1.

[0027] 1, it was revealed that the dissolution rate after storage decreased in the rasagiline mesylate-containing formulation of Comparative Example 1, which contained stearic acid 50. Based on the results of Comparative Example 1, it was investigated whether the delay in dissolution of rasagiline could be suppressed by including only a lubricant with a melting point or freezing point of 57°C or higher in a rasagiline mesylate-containing formulation.

[0028] [Example 1] In Example 1, a formulation containing rasagiline mesylate was produced using stearic acid 70. Specifically, 1.56 g of rasagiline mesylate, 138.8 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 (registered trademark) C, Nippon Starch Chemical Co., Ltd.) were charged into a mixing and kneading apparatus (HSM-2L, Earth Technica Co., Ltd.) and mixed, and purified water was added and mixed. The mixture was then dried in a fluidized bed granulator (MP-01, Powrex Corporation), and the resulting granules were sized using a granulator (Power Mill, Dalton Corporation). 9.0 g of D-mannitol (Granutol-S, Freund Corporation), 1.0 g of light anhydrous silicic acid (Adsolider® 101, Freund Corporation), 4.0 g of stearic acid 70 (Japanese Pharmacopoeia Stearic Acid 70, Kao Corporation), and 4.0 g of talc (Fuji Talc Industries Co., Ltd.) were homogeneously mixed to obtain a pre-tabletting powder. The pre-tabletting powder was compressed into tablets (210 mg per tablet) using a tablet press (VELA5, Kikusui Seisakusho Co., Ltd.) to produce the rasagiline mesylate-containing formulation of Example 1.

[0029] [Example 2] The rasagiline mesylate-containing formulation of Example 2 was produced in the same manner as in Example 1, except that stearic acid 70 was changed to stearic acid 95 (Japanese Pharmacopoeia Stearic Acid NAA (registered trademark)-180P-1, NOF Corporation).

[0030] The rasagiline mesylate-containing formulations of Examples 1 and 2 were sealed in an ultra-high moisture-proof sheet (Sumilite (registered trademark) FCL-1135, Sumitomo Bakelite Co., Ltd.) and stored for 1 week under conditions of 60°C and 60% RH. The dissolution rates of the rasagiline mesylate-containing formulations of Examples 1 and 2 immediately after production (initial) and after storage were calculated by the dissolution test method described above. The dissolution rates of the rasagiline mesylate-containing formulations of Examples 1 and 2 immediately after production (initial) and after storage are shown in Figures 2 and 3.

[0031] Comparative Example 2 In Comparative Example 2, stearic acid 50 was replaced with hydrogenated oil. Specifically, 1.56 g of rasagiline mesylate, 138.8 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 (registered trademark) C, Nippon Starch Chemical Co., Ltd.) were charged into a stirring and kneading apparatus (HSM-2L, Earth Technica Co., Ltd.) and mixed, and purified water was added and stirred and kneaded. The mixture was then dried using a fluidized bed granulator (MP-01, Powrex Corporation). The resulting granules were sized using a granulator (Power Mill, Dalton Corporation) and homogenized with 13.0 g of D-mannitol (Granutol-S, Freund Corporation), 1.0 g of light anhydrous silicic acid (Adsolider® 101, Freund Corporation), and 4.0 g of hydrogenated oil (K-3 Wax-500, Kawaken Fine Chemicals Co., Ltd.) to obtain a pre-tabletting powder. The pre-tabletting powder was compressed using a tablet press (VELA5, Kikusui Seisakusho Co., Ltd.) to yield a rasagiline mesylate-containing formulation of Comparative Example 2. Note that while talc was added in Examples 1 and 2, it was not added in Comparative Example 2 because, as is clear from the results of Comparative Example 1, the presence or absence of talc did not affect the dissolution properties of rasagiline.

[0032] Comparative Example 3 As Comparative Example 3, a rasagiline mesylate-containing formulation of Comparative Example 3 was produced in the same manner as in Comparative Example 2, except that the hydrogenated oil was changed to a sucrose fatty acid ester (Surfhope J-1816F, Mitsubishi Chemical Foods Corporation).

[0033] The rasagiline mesylate-containing formulations of Comparative Examples 2 and 3 were sealed in an ultra-high moisture-proof sheet (Sumilite (registered trademark) FCL-1135, Sumitomo Bakelite Co., Ltd.) and stored for one week under conditions of 60°C and 60% RH. A dissolution test was conducted on the rasagiline mesylate-containing formulations of Comparative Examples 2 and 3 immediately after production (initial) and after storage using a dissolution tester (Toyama Sangyo Co., Ltd.) in accordance with Method 2 of the dissolution test in the 18th Edition of the Japanese Pharmacopoeia (paddle method, 50 rpm) using 900 ml of water as the test medium. The dissolution properties of rasagiline do not depend on the pH of the test medium. The dissolution test was conducted three times using one tablet of each of the rasagiline mesylate-containing formulations of Comparative Examples 2 and 3 as a sample, and the average value was used as the dissolution rate. The dissolution rates of the rasagiline mesylate-containing formulations of Comparative Examples 2 and 3 immediately after production (initial) and after storage are shown in Figures 4 and 5.

[0034] 1 to 5, the delayed dissolution of rasagiline after storage was improved in the rasagiline mesylate-containing formulation of Example 1 containing 70% stearic acid and the rasagiline mesylate-containing formulation of Example 2 containing 95% stearic acid. In particular, the dissolution after storage of the rasagiline mesylate-containing formulation of Example 2 containing 95% stearic acid was equivalent to the initial dissolution. On the other hand, the dissolution of rasagiline after storage was delayed in the rasagiline mesylate-containing formulation of Comparative Example 2 containing hydrogenated oil as a lubricant and the rasagiline mesylate-containing formulation of Comparative Example 3 containing a sucrose fatty acid ester as a lubricant, despite the additives having a melting point or freezing point of 57°C or higher.

[0035] [Reference example 1] In Reference Example 1, a rasagiline mesylate-containing formulation was produced using sodium stearyl fumarate as a lubricant. Specifically, 1.56 g of rasagiline mesylate, 138.8 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 (registered trademark) C, Nippon Starch Chemical Co., Ltd.) were charged into a mixing and kneading apparatus (HSM-2L, Earth Technica Co., Ltd.) and mixed, and purified water was added and mixed. Thereafter, the mixture was dried in a fluidized bed granulator (MP-01, Powrex Corporation), and the resulting granules were sized using a granulator (Power Mill, Dalton Corporation). 13.0 g of D-mannitol (Granutol-S, Freund Corporation), 1.0 g of light anhydrous silicic acid (Adsolider (registered trademark) 101, Freund Corporation), and 2.0 g of sodium stearyl fumarate (PRUV (registered trademark), Rettenmeyer Japan Co., Ltd.) were mixed, and the pre-tabletting powder was compressed into tablets weighing 210 mg per tablet, thereby producing the rasagiline mesylate-containing formulation of Reference Example 1.

[0036] [Reference example 2] As Reference Example 2, a rasagiline mesylate-containing formulation of Reference Example 2 was produced by the same manufacturing method as Reference Example 1, except that sodium stearyl fumarate was changed to magnesium stearate (Taihei Chemical Industry Co., Ltd., plant).

[0037] [Stability evaluation] The rasagiline mesylate-containing formulations of Example 2 and Reference Examples 1 and 2 were sealed in aluminum pillows and stored for two weeks at 40°C and 75% RH. The amount (%) of rasagiline-related substances in the rasagiline mesylate-containing formulations of Example 2 and Reference Examples 1 and 2 after storage was measured. A mixture containing 1 mg of rasagiline was weighed out, and approximately 20 ml of a 4:1 mixture of phosphate aqueous solution and methanol was added 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 aliquot of the sample solution. Using the area percentage method, the sum of the peak areas of rasagiline and rasagiline-derived related substances on the chromatogram was set to 100, and the amount (%) of rasagiline-derived related substances was calculated from the peak area ratio. The calculated amounts of related substances are shown in Table 2.

[0038] [Table 2] [Table 2]

[0039] The results in Table 2 clearly show that the rasagiline mesylate-containing formulations of Reference Example 1, which contains sodium stearyl fumarate as a lubricant, and Reference Example 2, which contains magnesium stearate, show an increase in related substances after storage. The rasagiline-containing formulation described in Patent Document 2 contains sodium stearyl fumarate and / or magnesium stearate to improve disintegration, but the inclusion of a carboxylic acid is necessary to suppress the formation of related substances. On the other hand, the rasagiline mesylate-containing formulation of the present invention not only suppresses dissolution delay but also significantly suppresses the formation of related substances, eliminating the need for the addition of a carboxylic acid. Therefore, the rasagiline mesylate-containing formulation of the present invention can suppress dissolution delay without the addition of additives that do not need to be ingested by patients.

Claims

1. A rasagiline mesylate-containing formulation comprising rasagiline mesylate and a pharmaceutically acceptable lubricant having a stearic acid content of 60.0% or more.

2. The rasagiline mesylate-containing formulation according to claim 1, wherein the lubricant comprises one or more lubricants selected from the group consisting of 70% stearic acid and 95% stearic acid.

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