Mirabegron-containing preparation

Abstract

One embodiment of the present invention provides a mirabegron-containing preparation that suppresses formation of N-nitroso mirabegron. A mirabegron-containing preparation according to one embodiment of the present invention includes a mirabegron-containing tablet, blister packaging that accommodates and encloses the mirabegron-containing tablet, pillow packaging that encloses the blister packaging that accommodates the mirabegron-containing tablet, and a zeolite that is provided in the space between the blister packaging and the pillow packaging. The N-nitroso mirabegron content of the mirabegron-containing tablet after storage for 3 months at 40°C and a relative humidity of 75% may be 50% or less of an acceptable limit value for N-nitroso mirabegron.

Description

Mirabegron-containing preparations

[0001] One embodiment of the present invention relates to a mirabegron-containing preparation in which the production of N-nitrosomirabegron is suppressed.

[0002] Mirabegron (2-(2-Amino-1,3-thiazol-4-yl)-N-[4-(2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl)phenyl]acetamide) is a selective β ３ It has receptor stimulating effects and is an effective drug for treating overactive bladder.

[0003] On the other hand, it is known that mirabegron produces a nitroso compound, N-nitrosomirabegron (Non-Patent Document 1). Nitrosamines, a type of nitroso compound, are a group of amine derivatives in which the hydrogen on the amine nitrogen is replaced with a nitroso group, and some nitrosamines are known to be carcinogenic.

[0004] The European Medicines Agency (EMA) has set the acceptable intake of N-nitrosomirabegron at 400 ng / day (Non-Patent Document 2). The U.S. Food and Drug Administration (FDA) has also set the acceptable intake of N-nitrosomirabegron at 400 ng / day (Updated Information | Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs)). Since the maximum daily dose of mirabegron is 50 mg / day, the acceptable limit of N-nitrosomirabegron calculated from the maximum daily dose is 8 ppm.

[0005] Therefore, it is necessary to suppress the production of N-nitrosomirabegron in mirabegron-containing preparations to 8 ppm or less, but no method for suppressing the production of N-nitromirabegron has been known so far.

[0006] Schmidtsdorff S, et al. Risk assessment for nitrosated pharmaceuticals: A future perspective in drug development. Arch Pharm 2022;355(4).Questions and answers for marketing authorization holders / applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726 / 2004 referral on nitrosamine impurities in human medicinal products.

[0007] One object of one embodiment of the present invention is to provide a mirabegron-containing preparation in which the production of N-nitrosomirabegron is suppressed.

[0008] A mirabegron-containing formulation according to one embodiment of the present invention comprises a mirabegron-containing tablet, a blister package that houses and seals the mirabegron-containing tablet, a pillow package that seals the blister package that houses the mirabegron-containing tablet, and zeolite placed in the space between the blister package and the pillow package.

[0009] The content of N-nitrosomirabegron contained in the mirabegron-containing tablet when the mirabegron-containing formulation is stored for 3 months under conditions of 40°C and 75% relative humidity may be 50% or less of the allowable limit of N-nitrosomirabegron.

[0010] The content of N-nitrosomirabegron contained in the mirabegron-containing tablet when the mirabegron-containing formulation is stored for 6 months under conditions of 40°C and 75% relative humidity may be equal to or less than the allowable limit value of N-nitrosomirabegron.

[0011] The mirabegron-containing tablet may comprise a granulation containing mirabegron, polyethylene glycol and polyethylene oxide, and one or more pharmaceutically acceptable additives.

[0012] According to one embodiment of the present invention, there is provided a mirabegron-containing formulation in which the production of N-nitrosomirabegron is suppressed.

[0013] 1 is a schematic diagram illustrating a mirabegron-containing formulation according to one embodiment. 2 is a schematic diagram illustrating a blister package that houses and seals a mirabegron-containing tablet according to one embodiment.

[0014] The mirabegron-containing formulation of the present invention will be described below with reference to the drawings. It should be noted that the mirabegron-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 below, identical parts or parts having similar functions are designated by the same reference numerals, and repeated explanations thereof will be omitted.

[0015] As mentioned above, to meet the acceptable daily intake of 400 ng of N-nitrosomirabegron, the amount of N-nitrosomirabegron contained in mirabegron-containing tablets at the time of administration must be 8 ppm or less. Considering that the threshold for reporting the amount of related substances in pharmaceutical preparations is generally 1,000 ppm, the acceptable daily intake of N-nitrosomirabegron is a very strict standard.

[0016] As a result of studies conducted by the present inventors, the present inventors have found that the production of N-nitrosomirabegron in mirabegron-containing tablets can be suppressed by sealing the mirabegron-containing tablets using a desiccant, particularly zeolite. On the other hand, desiccants other than zeolite were unable to suppress the production of N-nitrosomirabegron. Furthermore, this result was independent of the efficacy of the desiccant (i.e., the equilibrium relative humidity of the formulation). There have been no reports of the suppression of N-nitrosomirabegron production being specific to the type of desiccant, independent of the equilibrium relative humidity of the mirabegron-containing formulation.

[0017] [Mirabegron-containing formulation] Fig. 1 is a schematic diagram illustrating a mirabegron-containing formulation 100 and a mirabegron-containing tablet 10 according to one embodiment. Fig. 2 is a schematic diagram illustrating a blister package 101 that houses and seals the mirabegron-containing tablet 10 according to one embodiment.

[0018] A mirabegron-containing formulation 100 according to one embodiment of the present invention comprises a mirabegron-containing tablet 10, a blister package 101 that contains and seals the mirabegron-containing tablet 10, a pillow package 103 that seals the blister package 101 that contains the mirabegron-containing tablet 10, and zeolite 105 that is placed in the space between the blister package 101 and the pillow package 103.

[0019] The mirabegron-containing tablet 10 used in this embodiment is not particularly limited and is a tablet containing 25 mg or 50 mg of mirabegron per tablet. In one embodiment, the mirabegron-containing tablet 10 contains a granulated product containing mirabegron, polyethylene glycol (also known as macrogol), and polyethylene oxide, and one or more pharmaceutically acceptable additives.

[0020] The mirabegron-containing tablet 10 may contain a lubricant as one or more pharmaceutically acceptable additives. Examples of lubricants include metal stearates, sucrose fatty acid esters, talc, light anhydrous silicic acid, hydrous silicon dioxide, and hardened oils. As the lubricant, metal stearates are preferred, and magnesium stearate is more preferred.

[0021] In one embodiment, the mirabegron-containing tablet 10 may contain an antioxidant as one or more pharmaceutically acceptable additives, such as dibutylhydroxytoluene (BHT).

[0022] In this embodiment, the blister package 101 is a sheet-like container that houses and seals the mirabegron-containing tablet 10. The mirabegron-containing tablet 10 is housed in an airtight state in the blister package 101. In this specification, the term "airtight state" refers to a state in which solid or liquid foreign matter cannot enter and loss, efflorescence, deliquescence, or evaporation of the contained pharmaceutical product can be prevented.

[0023] In one embodiment, the blister package 101 may be a composite sheet of a film selected from polyvinyl chloride film, polyvinylidene chloride film, polychlorotrifluoroethylene film, and polypropylene, or may be a PTP packaging sheet in which the opening of a container made of the above-mentioned film is sealed with aluminum foil.

[0024] In this embodiment, the pillow package 103 is a container that seals the blister package 101 containing the mirabegron-containing tablet 10. The blister package 101 is contained in the pillow package 103 in an airtight state. In one embodiment, the pillow package 103 may be an aluminum pillow package. The pillow package 103 has excellent sealing properties, so that the pillow package 103 can be prevented from being affected by moisture absorption from the external environment during storage. The aluminum pillow package may be any pillow package formed from a film having an aluminum layer, and may be a pillow package formed from a laminate film (laminate film) of aluminum foil and a plastic film, or a pillow package formed from a plastic film having an aluminum vapor-deposited film (aluminum vapor-deposited film). Examples of plastic films include films formed from polyolefins such as polyethylene and polypropylene; films formed from polyesters such as polyethylene terephthalate; and polyamide films formed from polyamides such as polyamide 6.

[0025] In this embodiment, the zeolite 105 is a desiccant placed in the space between the blister package 101 and the pillow package 103. The zeolite 105 may be synthetic zeolite 4A. The zeolite 105 preferably has a shape in which zeolite particles are wrapped in a film. For example, the film may be a polypropylene film. For example, MS-Ceram-W 3G manufactured by Tokai Chemical Industry Co., Ltd. may be used as the zeolite 105.

[0026] Known desiccants used in formulations include calcium chloride (e.g., ID (registered trademark) Sheet from ID Corporation) and oxygen absorbers (e.g., PharmaKeep (registered trademark) from Mitsubishi Gas Chemical Company, Inc.). However, in this embodiment, as shown in the examples described later, the use of zeolite can specifically suppress the production of N-nitrosomirabegron.

[0027] In the mirabegron-containing formulation 100 according to this embodiment, the content of N-nitrosomirabegron contained in the mirabegron-containing tablet 10 after storage for 3 months under conditions of 40°C and 75% relative humidity is 50% or less, preferably 42% or less, of the allowable limit of N-nitrosomirabegron. In this specification, the content of N-nitrosomirabegron is measured using liquid chromatography.

[0028] In one embodiment, when the mirabegron-containing formulation 100 according to this embodiment is stored for 6 months under conditions of 40°C and 75% relative humidity, the content of N-nitrosomirabegron contained in the mirabegron-containing tablet 10 is equal to or less than the allowable limit of N-nitrosomirabegron. More specifically, when the mirabegron-containing formulation 100 according to this embodiment is stored for 6 months under conditions of 40°C and 75% relative humidity, the content of N-nitrosomirabegron contained in the mirabegron-containing tablet 10 is, for example, 99% or less, preferably 42% or less, of the allowable limit of N-nitrosomirabegron.

[0029] In one embodiment, the mirabegron-containing formulation 100 may be housed in, for example, a paper box, which may be further covered with a vinyl film.

[0030] [Mirabegron-Containing Tablets] 50 g of mirabegron, 70 g of polyethylene oxide, and 120 g of macrogol 6000 were mixed in a fluidized bed granulator (model: MP-01, Powrex Corporation) and granulated using a solution prepared by dissolving 8 g of hydroxypropyl cellulose in 68 g of 50% ethanol. The resulting granules were sieved through a No. 22 sieve to obtain a sieved product. 247 g of the sieved product, 1 g of dibutylhydroxytoluene, and 3 g of magnesium stearate were mixed in a plastic bag and compressed into tablets of 250 mg each using a rotary tablet press (VELA5, Kikusui Seisakusho Co., Ltd.). A film coating solution prepared by dissolving or dispersing 25 g of hypromellose, 5 g of macrogol 6000, 2 g of titanium oxide, and 6 g of yellow ferric oxide in 350 g of purified water was applied to each tablet in an amount of 0.03 parts by weight to produce mirabegron-containing tablets. Each tablet contains 50 mg of mirabegron.

[0031] Comparative Example 1 The prepared mirabegron-containing tablets were sealed in a PTP packaging sheet and further sealed in an aluminum pillow to prepare a mirabegron-containing formulation of Comparative Example 1.

[0032] Comparative Example 2 The PTP packaging sheet in which the mirabegron-containing tablets prepared in Comparative Example 1 had been sealed was further sealed in an aluminum pillow together with calcium chloride (ID (registered trademark) sheet from ID Co., Ltd.) as a desiccant to prepare the mirabegron-containing formulation of Comparative Example 2.

[0033] Comparative Example 3 The PTP packaging sheet in which the mirabegron-containing tablets prepared in Comparative Example 1 had been sealed was further sealed in an aluminum pillow together with an oxygen absorber (PharmaKeep (registered trademark) from Mitsubishi Gas Chemical Company, Inc.) as a desiccant to prepare the mirabegron-containing formulation of Comparative Example 3.

[0034] Example 1 The mirabegron-containing tablet prepared in Comparative Example 1 was sealed in a PTP packaging sheet, which was further sealed in an aluminum pillow together with zeolite (MS-Ceram-W 3G, manufactured by Tokai Chemical Industry Co., Ltd.) as a desiccant, to prepare the mirabegron-containing formulation of Example 1.

[0035] The mirabegron-containing formulations of Comparative Examples 1 to 3 were stored for 1 month and 3 months under conditions of 40°C and 75% relative humidity, respectively. The mirabegron-containing formulation of Example 1 was stored for 1 month, 3 months, and 6 months under conditions of 40°C and 75% relative humidity.

[0036] [Measurement of equilibrium relative humidity (ERH)] Using a moisture measuring device (Hygrolab2) manufactured by Rotronic, the ERH of the mirabegron-containing tablets of Comparative Examples 1 to 3 and Example 1 during storage was measured. Specifically, five tablets each of the mirabegron-containing tablets of Comparative Examples 1 to 3 and Example 1 stored under the above conditions were placed in a sample cup, set in a measurement chamber, and measured at room temperature. The ERH and temperature at the time when the relative humidity reached equilibrium were recorded. The average values ​​of the measured ERH and temperature were converted to ERH at 24°C using the following formula. The measurement results are shown in Table 1. T: Average temperature during measurement E: Average ERH value measured Ps: Saturated vapor pressure at the measured temperature P: Vapor pressure at the measured temperature H: Absolute humidity at the measured temperature Ps [kPa] = 0.611 * 10^(7.5 * T / (T + 237.3)) P [kPa] = E / 100 * Ps H [kg / kgDA] = 0.62 * P / (101.3 - P) ERH [% RH] at 24°C = H * 101.3 / (H + 0.62) * 2.98

[0037] [Quantitative Analysis of N-Nitrosomirabegron] Five mirabegron-containing tablets immediately after production, five mirabegron-containing tablets from Comparative Examples 1 to 3 stored under the above conditions for 1 month and 3 months, and five mirabegron-containing tablets from Example 1 stored under the above conditions for 1 month, 3 months, and 6 months were placed in a light-shielding container and finely pulverized. A powder equivalent to 50 mg of mirabegron was precisely weighed and placed in a 20 ml flask, and 10 ml of methanol was added to make exactly 20 ml. This solution was centrifuged, and 5 ml of the supernatant was accurately measured. Then, exactly 5 ml of water was added, followed by a dilution solvent of a water / ethanol mixture (1:1) to make exactly 50 ml. This solution was filtered through a membrane filter with a pore size of 0.45 μm or less. The first 5 ml or more of the filtrate was removed, and the next filtrate was used as the sample solution.

[0038] Separately, approximately 10 mg of N-nitrosomirabegron was accurately weighed and methanol was added to make exactly 100 ml (0.1 mg / ml). 2 ml of this solution was accurately weighed and 2 ml of water was added, followed by dilution solvent to make exactly 100 ml (2 μg / ml). 2 ml of this solution was accurately weighed and dilution solvent was added to make exactly 200 ml to obtain a standard stock solution (20 ng / ml). 1 ml, 2 ml, 6 ml, 10 ml, 14 ml, 20 ml, and 24 ml of the standard stock solution were accurately weighed and dilution solvent was added to make exactly 200 ml, respectively, to prepare 5%, 10%, 30%, 50%, 70%, 100%, and 120% standard solutions.

[0039] 10 μl of each sample solution and standard solution was accurately taken and measured by liquid chromatography under the conditions below. The peak area of ​​each solution was measured by automatic integration, and a calibration curve was created from the peak area of ​​N-nitrosomirabegron obtained from each standard solution, with the vertical axis representing the peak area and the horizontal axis representing the standard solution concentration (%). The peak area Ar of N-nitrosomirabegron obtained from the sample solution was then matched to this curve, and the amount of N-nitrosomirabegron relative to the amount of mirabegron drug substance was calculated using the following formula. The measurement results are shown in Table 1 as a percentage (%) of the acceptable limit of N-nitrosomirabegron. Amount of N-nitrosomirabegron (ppm) relative to the amount of mirabegron drug substance = (Ar - b) / a * Ms * M Ｔ２ / M Ｔ１ *2 / 250 a: Slope of the calibration curve b: Y-intercept of the calibration curve Ms: Amount of N-nitrosomirabegron (mg) M Ｔ１ M: Actual weighed amount (g) of sample equivalent to 50 mg of mirabegron Ｔ２ : Theoretical weighed amount (g) of sample equivalent to 50 mg of mirabegron 2 / 250: Correction coefficient

[0040]

[0041] Table 1 shows the percentage of N-nitrosomirabegron contained in each sample, assuming the allowable limit of N-nitrosomirabegron as 100%. The results in Table 1 demonstrate that the production of N-nitrosomirabegron was significantly suppressed in the mirabegron-containing formulation of Example 1, which used zeolite as a desiccant. On the other hand, the production of N-nitrosomirabegron was not effectively suppressed in the mirabegron-containing formulation of Comparative Example 1, which did not use a desiccant; the mirabegron-containing formulation of Comparative Example 2, which used calcium chloride as a desiccant; and the mirabegron-containing formulation of Comparative Example 3, which used an oxygen scavenger as a desiccant.

[0042] Furthermore, although the ERH value in Comparative Example 3 was close to that in Example 1, the amount of N-nitrosomirabegron produced was greater than in Comparative Examples 1 and 2, which had higher ERH levels, demonstrating that the production of N-nitrosomirabegron cannot be effectively suppressed by controlling ERH.

[0043] Furthermore, the N-nitrosomirabegron contained in the mirabegron-containing tablets of Example 1 remained well below the tolerable intake of N-nitrosomirabegron even after storage under the accelerated test conditions (40°C, 75% RH, 6 months) of the Stability Test Guidelines (Yaku Shinyaku No. 30, dated April 21, 1994), which stipulates the handling of stability test results that must be attached when applying for approval to manufacture pharmaceuticals.

[0044] 10 Mirabegron-containing tablet, 100 Mirabegron-containing preparation, 101 Blister packaging, 103 Pillow packaging, 105 Zeolite

Claims

1. A mirabegron-containing formulation comprising: a mirabegron-containing tablet; a blister package that houses and seals the mirabegron-containing tablet; a pillow package that seals the blister package that houses the mirabegron-containing tablet; and zeolite placed in the space between the blister package and the pillow package.

2. The mirabegron-containing formulation according to claim 1, wherein the content of N-nitrosomirabegron contained in the mirabegron-containing tablet is 50% or less of the allowable limit of N-nitrosomirabegron when the mirabegron-containing formulation is stored for 3 months under conditions of 40°C and 75% relative humidity.

3. The mirabegron-containing formulation according to claim 1, wherein the content of N-nitrosomirabegron contained in the mirabegron-containing tablet is below the allowable limit of N-nitrosomirabegron when the mirabegron-containing formulation is stored for 6 months under conditions of 40°C and 75% relative humidity.

4. The mirabegron-containing formulation according to any one of claims 1 to 3, wherein the mirabegron-containing tablet comprises a granulation containing mirabegron, polyethylene glycol, and polyethylene oxide, and one or more pharmaceutically acceptable additives.

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