Release-controlled pharmaceutical composition

Abstract

To provide a novel controlled-release pharmaceutical composition comprising mirabegron or a pharmaceutically acceptable salt thereof, with improved stability.SOLUTION: A controlled-release pharmaceutical composition comprises mirabegron or a pharmaceutically acceptable salt thereof, a hydrogel-forming polymer, and a hydrophilic base. The hydrophilic base comprises at least one selected from the group consisting of sodium benzoate, trehalose, erythritol, maltitol, α-cyclodextrin, and aspartame.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to a release-controlled pharmaceutical composition containing mirabegron or a pharmaceutically acceptable salt thereof. The present invention also relates to a method for producing the release-controlled pharmaceutical composition.

Background Art

[0002] Mirabegron or a pharmaceutically acceptable salt thereof has a β3 - adrenergic receptor agonist action and is useful as a therapeutic agent for overactive bladder.

[0003] As a formulation containing mirabegron or a pharmaceutically acceptable salt thereof, for example, in Patent Document 1, there is disclosed an orally administered release-controlled pharmaceutical composition containing mirabegron or a pharmaceutically acceptable salt thereof, one or more specific additives having specific parameters, and a polymer substance forming a specific hydrogel having a specific dissolution rate.

Prior Art Documents

Patent Documents

[0004] [[ID=2�]]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0005] However, the formulation as described in Patent Document 1 had room for improvement from the viewpoint of stability.

[0006] Therefore, one aspect of the present invention aims to realize a novel release-controlled pharmaceutical composition containing mirabegron or a pharmaceutically acceptable salt thereof with improved stability. Another aspect of the present invention aims to realize a method for producing a release-controlled pharmaceutical composition containing mirabegron or a pharmaceutically acceptable salt thereof.

Means for Solving the Problems

[0007] As a result of diligent research to solve the above problems, the present inventors have discovered for the first time that the stability of mirabegron or a pharmaceutically acceptable salt thereof can be improved by using a specific hydrophilic base in a release-controlled pharmaceutical composition comprising mirabegron or a pharmaceutically acceptable salt thereof, a hydrogel-forming polymer, and a hydrophilic base, thereby completing the present invention. That is, one aspect of the present invention includes the following configuration. <1> A controlled-release pharmaceutical composition comprising mirabegron or a pharmaceutically acceptable salt thereof, a hydrogel-forming polymer, and a hydrophilic base, A controlled-release pharmaceutical composition wherein the hydrophilic base comprises at least one selected from the group consisting of sodium benzoate, trehalose, erythritol, maltitol, α-cyclodextrin, and aspartame. <2> The content of the hydrophilic base is 4 to 49% by weight. <1> The release-controlled pharmaceutical composition described above. <3> The hydrogel-forming polymer is polyethylene oxide. <1> or <2> The release-controlled pharmaceutical composition described above. <4> The content of the hydrogel-forming polymer is 28-74% by weight. <1> ~ <3> A controlled-release pharmaceutical composition as described in any of the following. <5> It is a tablet. <1> ~ <4> A controlled-release pharmaceutical composition as described in any of the following. <6> The gelation rate in water is 55.0-85.0%, and / or the gel strength in water is 3.0-25.5 g. <5> The release-controlled pharmaceutical composition described above. <7> A method for producing a controlled-release pharmaceutical composition, comprising the step of blending mirabegron or a pharmaceutically acceptable salt thereof, a hydrogel-forming polymer, and a hydrophilic base, A method for producing the hydrophilic base, wherein the hydrophilic base comprises at least one selected from the group consisting of sodium benzoate, trehalose, erythritol, maltitol, α-cyclodextrin, and aspartame. [Effects of the Invention]

[0008] According to one aspect of the present invention, a novel controlled-release pharmaceutical composition with improved stability, comprising mirabegron or a pharmaceutically acceptable salt thereof, can be provided. [Brief explanation of the drawing]

[0009] [Figure 1] This figure shows the results of an elution test according to an embodiment of the present invention. [Modes for carrying out the invention]

[0010] [1. Outline of the present invention] A controlled-release pharmaceutical composition according to one embodiment of the present invention (hereinafter referred to as "the pharmaceutical composition") comprises mirabegron or a pharmaceutically acceptable salt thereof, a hydrogel-forming polymer, and a hydrophilic base, wherein the hydrophilic base comprises at least one selected from the group consisting of sodium benzoate, trehalose, erythritol, maltitol, α-cyclodextrin, and aspartame.

[0011] Furthermore, a method for producing a release-controlled pharmaceutical composition according to one embodiment of the present invention (hereinafter referred to as "this production method") is a method for producing a release-controlled pharmaceutical composition, comprising the step of blending mirabegron or a pharmaceutically acceptable salt thereof, a hydrogel-forming polymer, and a hydrophilic base, wherein the hydrophilic base comprises at least one selected from the group consisting of sodium benzoate, trehalose, erythritol, maltitol, α-cyclodextrin, and aspartame.

[0012] Conventionally, a release-controlled pharmaceutical composition was known in which polyethylene glycol (PEG) or the like was added as a hydrophilic agent to a gel matrix pharmaceutical composition containing mirabegron and polyethylene oxide as a sustained-release agent (for example, Patent Document 1). In the course of investigating formulations containing mirabegron, the present inventors discovered a novel problem: PEG has poor compatibility with mirabegron, leading to a decrease in the stability of the pharmaceutical composition.

[0013] In order to solve the above-mentioned new problems in detail from the perspective of stability, the present inventors have conducted a detailed examination. As a result, in a controlled-release pharmaceutical composition containing mirabegron or a pharmaceutically acceptable salt thereof, a hydrogel-forming polymer, and a hydrophilic base, by using a specific hydrophilic base (for example, sodium benzoate, trehalose, erythritol, maltitol, α-cyclodextrin, and aspartame), they have succeeded in obtaining the finding that the stability of mirabegron or a pharmaceutically acceptable salt thereof is improved. Further, it has been shown that the above-mentioned controlled-release pharmaceutical composition also exhibits effects equivalent to or greater than those of a controlled-release pharmaceutical composition containing a conventional hydrophilic base (polyethylene glycol) in terms of gelation rate, gel strength, disintegration time, and elution property.

[0014] Heretofore, it has not been known that a hydrophilic base can contribute to the stabilization of mirabegron or a pharmaceutically acceptable salt thereof. Among such circumstances, it is surprising that the present inventors focused on the hydrophilic base among many components that can be included in a controlled-release pharmaceutical composition, and further, by selecting and using a specific hydrophilic base, they were able to achieve an improvement in the stability of mirabegron or a pharmaceutically acceptable salt thereof.

[0015] Thus, since this pharmaceutical composition exhibits advantageous effects based on the above findings, it is possible to provide a novel and extremely useful controlled-release pharmaceutical composition containing mirabegron or a pharmaceutically acceptable salt thereof. Further, in one aspect of the present invention, it is possible to provide a method for producing a controlled-release pharmaceutical composition containing mirabegron or a pharmaceutically acceptable salt thereof.

[0016] [2. Controlled-Release Pharmaceutical Composition] In the present specification, the "controlled-release pharmaceutical composition" means a preparation in which the drug elution rate from the preparation after 30 minutes from the start of the test is less than 85% when an elution test is carried out under any of the following conditions. · Using 900 mL of an appropriate test solution (for example, Mc.Ilvain buffer solution at pH 7.5), an elution test is carried out at a rotation speed of 50 rotations per minute according to the second method of the Japanese Pharmacopoeia elution test.

[0017] Specifically, the "drug-releasing controlled pharmaceutical composition" is a preparation that combines an additive (hydrophilic base) for allowing water to penetrate into the preparation and a hydrogel-forming polymer.

[0018] (Mirabegron or a pharmaceutically acceptable salt thereof) This pharmaceutical composition contains mirabegron or a pharmaceutically acceptable salt thereof as an active ingredient. As an example of mirabegron or a pharmaceutically acceptable salt thereof, (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide having the structure of the following formula (1) can be mentioned.

[0019] [Chemical formula]

[0020] <000010​​​​​​​​​​) is preferably 3 μm or more and 30 μm or less, more preferably 5 μm or more and 25 μm or less, and even more preferably 8 μm or more and 20 μm or less. In this specification, this D 50 This is based on the volume-based particle size distribution measured using a laser diffraction / scattering particle size distribution analyzer. Examples of laser diffraction / scattering particle size distribution analyzers include Microtrac-Bell's "Aerotrac LDSA-SPR" and Malvern Panalytical's "Mastersizer 3000".

[0023] The content of mirabegron or a pharmaceutically acceptable salt in this pharmaceutical composition is, for example, 5 to 30% by weight, preferably 7 to 25% by weight, based on the mass of the pharmaceutical composition.

[0024] (Hydrophilic base) This pharmaceutical composition contains at least one hydrophilic agent selected from the group consisting of sodium benzoate, trehalose, erythritol, maltitol, α-cyclodextrin, and aspartame (hereinafter sometimes simply referred to as "hydrophilic agent"). The inclusion of the above-mentioned hydrophilic agent in this pharmaceutical composition improves the stability of mirabegron or its pharmaceutically acceptable salt.

[0025] In one embodiment of the present invention, the hydrophilic base is preferably sodium benzoate, erythritol, or maltitol, from the viewpoint of overall usefulness such as the stability and sustained release of mirabegron or a pharmaceutically acceptable salt thereof.

[0026] The hydrophilic base content in this pharmaceutical composition is preferably 4 to 49% by weight, more preferably 10 to 40% by weight, and even more preferably 15 to 35% by weight, based on the mass of the pharmaceutical composition.

[0027] In one embodiment of the present invention, the pharmaceutical composition may contain polyethylene glycol as a hydrophilic base, to the extent that it does not impair the effects of the pharmaceutical composition described above. However, from the viewpoint of improving the stability of the pharmaceutical composition, it is preferable that the pharmaceutical composition is substantially free of polyethylene glycol. In this specification, "substantially free of polyethylene glycol" means that the composition contains polyethylene glycol in an amount of 0.1% by weight or less, and may also be 0% by weight.

[0028] (Hydrogel-forming polymer) This pharmaceutical composition contains a hydrogel-forming polymer. The inclusion of this hydrogel-forming polymer gives the pharmaceutical composition sustained release properties, allowing for controlled release of the active ingredient within the composition.

[0029] The number-average molecular weight of the hydrogel-forming polymer is, for example, 100,000 or more, preferably 100,000 to 8,000,000, more preferably 100,000 to 5,000,000, and even more preferably 100,000 to 2,000,000. The viscosity of the hydrogel-forming polymer is, for example, 12 mPa·s or more when the 5% aqueous solution is at 25°C, preferably 12 mPa·s or more when the 5% aqueous solution is at 25°C and 40,000 mPa·s or less when the 1% aqueous solution is at 25°C, more preferably 400 mPa·s or more when the 2% aqueous solution is at 25°C and 7,500 mPa·s or less when the 1% aqueous solution is at 25°C, and even more preferably 400 mPa·s or more when the 2% aqueous solution is at 25°C and 5,500 mPa·s or less when the 1% aqueous solution is at 25°C. By adjusting the viscosity of the polymeric substance used as the hydrogel-forming polymer, the release period of the active ingredient from this pharmaceutical composition can be arbitrarily controlled.

[0030] The hydrogel-forming polymer is not particularly limited, but examples include polyethylene oxide, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, Carboxyvinyl polymer Examples include the following. Preferably, polyethylene oxide is used. One type of hydrogel-forming polymer may be used, or two or more types may be used.

[0031] Polyethylene oxide (hereinafter sometimes abbreviated as "PEO") includes, for example, the following product names: Polyox WSR-308 [number average molecular weight: 8 million, viscosity: 10,000-15,000 mPa·s (1% aqueous solution at 25℃)], Polyox WSR-303 [number average molecular weight: 7 million, viscosity: 7,500-10,000 mPa·s (1% aqueous solution at 25℃)], Polyox WSR Coagulant [number average molecular weight: 5 million, viscosity: 5,500-7,500 mPa·s (1% aqueous solution at 25℃)], Polyox WSR-301 [number average molecular weight: 4 million, viscosity: 1,650-5,500 mPa·s (1% aqueous solution at 25℃)], Polyox WSR-N-60K [number average molecular weight: 2 million, viscosity: 2,000-4,000 mPa·s (2% aqueous solution at 25℃)], Polyox WSR-N-12K [number average molecular weight: 1 million, viscosity: 400-800 mPa·s (2% aqueous solution at 25°C)], Polyox WSR-1105 [number average molecular weight: 900,000, viscosity: 8800-17600 mPa·s (5% aqueous solution at 25°C)], Polyox WSR-205 [number average molecular weight: 600,000, viscosity: 4500-8800 mPa·s (5% aqueous solution at 25°C)], Polyox WSR-N-750 [number average molecular weight: 300,000, viscosity: 600-1200 mPa·s (5% aqueous solution at 25°C)], Polyox WSR-N-80 [number average molecular weight: 200,000, viscosity: 55-90 mPa·s (5% aqueous solution 25°C)], Polyox Examples include WSR-N-10 [number-average molecular weight: 100,000, viscosity: 12-50 mPa·s (5% aqueous solution at 25℃)] (manufactured by DOW Corporation).

[0032] The hydrogel-forming polymer content in this pharmaceutical composition is preferably 28 to 74% by weight, more preferably 35 to 70% by weight, even more preferably 42 to 65% by weight, and particularly preferably 45 to 65% by weight, based on the mass of the pharmaceutical composition. When the hydrogel-forming polymer content is within the above range, this pharmaceutical composition has excellent sustained-release properties.

[0033] (Other ingredients) This pharmaceutical composition may also contain, in addition to the above-mentioned components, excipients, binders, lubricants, disintegrants, surfactants, plasticizers, colorants, etc.

[0034] Excipients are not particularly limited, but examples include D-mannitol, lactose (e.g., lactose monohydrate), sucrose, corn starch, calcium phosphate, sorbitol, crystalline cellulose, and light anhydrous silicic acid. Preferably, crystalline cellulose and lactose (e.g., lactose monohydrate) are used.

[0035] The binder is not particularly limited, but examples include hydroxypropylcellulose, hydroxypropylmethylcellulose (also called "hypromellose"), povidone, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, copolymers of N-vinylpyrrolidone and vinyl acetate, or combinations thereof, pregelatinized starch, gelatin, agar, gum arabic, etc. Hypromellose is preferably used. Hypromellose with a viscosity range of 80 to 140,000 mPa·s is preferably used, for example, hypromellose 2208 (Methocel(trademark) K4MPremiumCR, viscosity: 2,500 to 5,000 mPa·s).

[0036] The lubricant is not particularly limited, but examples include inert substances such as talc, kaolin, and titanium dioxide, magnesium stearate, calcium stearate, stearic acid, light anhydrous silicic acid, finely ground silicon dioxide, sodium stearyl fumarate, and glycerin fatty acid esters. Glycerin fatty acid esters are preferably used.

[0037] The disintegrant is not particularly limited, but examples include crospovidone, low-substituted hydroxypropylcellulose, sodium starch glycolate, croscarmellose sodium, carmellose, carmellose calcium, potato starch, etc. Crospovidone is preferably used.

[0038] The coloring agent is not particularly limited, but examples include yellow coloring agents (e.g., yellow iron(III) oxide, yellow iron oxide, food yellow No. 4 aluminum lake, red iron oxide, etc.), red coloring agents (e.g., iron(III) oxide, food red No. 2, food red No. 3, food red No. 102, etc.), black coloring agents (e.g., black iron oxide, carbon black, medicinal charcoal, etc.), blue coloring agents (e.g., blue No. 2 aluminum lake, etc.), caramel, etc. Preferably, yellow iron(III) oxide and blue No. 2 aluminum lake are used.

[0039] The content of each of the above-mentioned additives is not particularly limited and can be appropriately set based on conventionally known techniques.

[0040] (formulation) In one embodiment of the present invention, the pharmaceutical composition may be a tablet, capsule, granule, powder, suppository, etc. Preferably, the pharmaceutical composition is a tablet. Below, as an example, the case in which the pharmaceutical composition is a tablet will be described (hereinafter referred to as "the tablet").

[0041] The gelation rate of this tablet in water is preferably 55.0 to 85.0%, more preferably 56.0 to 83.0%, and even more preferably 57.0 to 81.0%. If the gelation rate of this tablet in water is within the above range, sustained release suitable for a sustained-release formulation can be ensured. The gelation rate of this tablet in water can be measured and evaluated by the method described in the examples below.

[0042] The gel strength of this tablet in water is preferably 3.0 to 25.5 g, more preferably 3.1 to 24.9 g, and even more preferably 3.2 to 24.8 g. If the gel strength of this tablet in water is within the above range, sustained release suitable for a sustained-release formulation can be ensured. The gel strength of this tablet in water can be measured and evaluated by the method described in the examples below.

[0043] The gelation rates of this tablet in a solution with a pH of 1.2, a solution with a pH of 4.0, and a solution with a pH of 6.8 are also based on the description of the gelation rate of this tablet in water. Furthermore, the gel strength of this tablet in a solution with a pH of 1.2, a solution with a pH of 4.0, and a solution with a pH of 6.8 are also based on the description of the gel strength of this tablet in water.

[0044] In one embodiment of the present invention, it is preferable that the gelation rate or gel strength in water of the tablet is within the preferred range described above, and it is more preferable that both the gelation rate and gel strength in water are within the preferred range described above.

[0045] In one embodiment of the present invention, it is preferable that the tablet satisfies the above-mentioned gel strength and / or gelation rate not only in water but also in low pH solutions (for example, pH 1.2, 4.0, 6.8).

[0046] The shape of the tablet can be appropriately selected, such as a round tablet or an irregularly shaped tablet. If the tablet is round, the diameter is not particularly limited, but for example it is 4 to 12 mm, preferably 6 to 10 mm. The thickness of the tablet is not particularly limited, but for example it is 3 to 12 mm, preferably 4 to 10 mm. If the tablet is irregularly shaped, its size is not particularly limited, but for example the long diameter is 10 to 15 mm, the short diameter is 4 to 8 mm, and the thickness is 3 to 10 mm.

[0047] In one embodiment of the present invention, the tablet contains, for example, 25 mg or 50 mg of mirabegron or a pharmaceutically acceptable salt thereof.

[0048] The amounts of each component contained in this tablet are based on the amounts of each component contained in the pharmaceutical composition described in [2. Release-Controlled Pharmaceutical Composition].

[0049] The shape of these tablets is not particularly limited and may be, for example, round, oval, spherical, rod-shaped, or donut-shaped.

[0050] These tablets may be further coated as needed. Known coating methods can be used for the coating. For example, pan coating, fluidized bed coating, etc., can be used. The coating agent can be appropriately selected from pharmaceutically acceptable ones depending on the application of the coating. Examples of coating agents include hypromellose, ethylcellulose, talc, titanium dioxide, silicic acid, hydroxypropylcellulose, polyvinylpyrrolidone, aminoalkyl methacrylate copolymer, polyvinyl alcohol, polyvinyl alcohol diethylaminoacetate, polyvinyl alcohol acetate phthalate, cellulose acetate phthalate, hypromellose phthalate, methacrylic acid copolymer, copolymer of methyl methacrylate and butyl methacrylate, and dimethylaminoethyl methacrylate. The coating agent may be used alone or in combination of two or more. Furthermore, these tablets may be packaged as needed in PTP (Press Through Pack) packaging, bottle filling, aluminum packaging, etc.

[0051] Examples of materials for PTP packaging include resins such as polyvinyl chloride, polypropylene, polyvinylidene chloride, polychlorotrifluoroethylene, polyethylene, polystyrene, or polycarbonate, as well as metals such as aluminum. These materials may be used individually or in combination. Examples of combinations include laminating polyvinyl chloride and polyvinylidene chloride, or laminating polyvinyl chloride and polychlorotrifluoroethylene. The above resins can be molded into resin sheets using known methods, and the tablets can be placed in molded pockets and sealed with aluminum foil.

[0052] The PTP packaging containing these tablets may be further packaged in an aluminum pillow. This aluminum pillow may further contain a desiccant. Examples of desiccants include calcium chloride, calcium oxide, magnesium oxide, silica gel, or zeolite.

[0053] [3. Manufacturing method] The present invention provides a method for producing a controlled-release pharmaceutical composition, comprising the step of blending mirabegron or a pharmaceutically acceptable salt thereof, a hydrogel-forming polymer, and a hydrophilic base, wherein the hydrophilic base comprises at least one selected from the group consisting of sodium benzoate, trehalose, erythritol, maltitol, α-cyclodextrin, and aspartame.

[0054] In this manufacturing method, the descriptions of each component (for example, "mirabegron or a pharmaceutically acceptable salt thereof," "hydrophilic base," and "hydrogel-forming polymer") are as provided in [2. Release-Controlled Pharmaceutical Compositions].

[0055] The compounding step of this manufacturing method can be carried out using any method used in the pharmaceutical field. Preferably, this manufacturing method is carried out by the method described in the examples.

[0056] Furthermore, the tablets can be obtained by, for example, compressing the controlled-release pharmaceutical composition obtained by this manufacturing method into single tablets.

[0057] The tablet compression pressure in this manufacturing method can be appropriately adjusted depending on the formulation and tablet shape, but is preferably in the range of 4 to 16 kN. Similarly, the tablet hardness can be appropriately adjusted depending on the purpose, but is preferably in the range of 20 to 200 N.

[0058] [4. Stabilization method] In one embodiment of the present invention, a method for stabilizing a release-controlled pharmaceutical composition comprising mirabegron or a pharmaceutically acceptable salt thereof, a hydrogel-forming polymer, and a hydrophilic base is provided, characterized in that the hydrophilic base comprises at least one selected from the group consisting of sodium benzoate, trehalose, erythritol, maltitol, α-cyclodextrin, and aspartame (hereinafter referred to as the stabilization method). In the stabilization method, the mirabegron or a pharmaceutically acceptable salt thereof can be stabilized by the above-mentioned specific hydrophilic base, which is advantageous in designing formulations containing mirabegron or a pharmaceutically acceptable salt thereof.

[0059] In this stabilization method, the descriptions of each component (e.g., "mirabegron or a pharmaceutically acceptable salt thereof," "hydrophilic base," "hydrogel-forming polymer") are as provided in [2. Release-Controlled Pharmaceutical Compositions].

[0060] The present invention is not limited to the embodiments described above, and various modifications are possible within the scope of the claims. Embodiments obtained by appropriately combining the technical means disclosed in different embodiments are also included in the technical scope of the present invention. [Examples]

[0061] One embodiment of the present invention is described below.

[0062] [Measurement and evaluation methods] The evaluations in the examples and comparative examples were carried out using the following method.

[0063] (Stability test) The stability of the pharmaceutical compositions prepared in Comparative Example 1 and Examples 1-6 was evaluated. Specifically, test tubes containing the pharmaceutical compositions were left open for two weeks at 40°C and 75% RH, or at 60°C and 2 weeks in a sealed container. After this, the pharmaceutical compositions or tablets were removed, and the amount of related substances (total related substances) was measured.

[0064] For each experimental example, the pharmaceutical composition or tablets were sonicated with a certain amount of extraction solvent (methanol), filtered through a membrane filter, and mobile phase A was added to obtain a sample solution. The above sample solution was subjected to HPLC under the following conditions, and the peak areas of mirabegron and related substances in each sample solution were measured by an automatic integration method, and the amount of related substances was calculated by the area percentage method: <HPLC measurement conditions> · Measurement wavelength: UV detector (measurement wavelength 250 nm) · Column: A stainless steel tube with an inner diameter of 2.1 mm and a length of 15 cm is filled with octadecylsilylated silica gel for liquid chromatography with a particle size of 1.7 μm. · Column temperature: 40 °C · Mobile phase A: A solution obtained by dissolving ammonium acetate in water and adjusting the pH with acetic acid (100%) · Mobile phase B: Methanol · Flow rate: 0.2 mL / min · Liquid delivery: By changing the mixing ratio of mobile phase A and mobile phase B, the concentration gradient was controlled.

[0065] (Gelation rate of tablets) The gelation rates of the tablets produced in Comparative Example 2 and Examples 7 to 12 were evaluated. Specifically, 900 mL of distilled water was placed in a beaker as a test solution, and the above tablets were added and allowed to stand. After 30 minutes, the tablets were taken out, and the gel layer was peeled off by hand. Then, the weight (W obs [[ID=XX]]) of the dried product of the non-gelled portion obtained was measured. From W obs obs , the gelation rate (G) was calculated according to the following formula (1). Also, for Comparative Example 2, Example 7, and Example 9, tests were also conducted using 900 mL of dissolution test solution No. 1 with a pH of 1.2, Mc.Ilvain buffer solution with a pH of 4.0, and dissolution test solution No. 2 with a pH of 6.8 instead of distilled water.

[0066] Gelation rate (G, %) = (1 - (W obs ) / (W ini )) × 100 ··· (1) W obs : Weight of the non-gelled portion after the start of the test W ini : Tablet weight before the start of the test (Gel strength of the tablet) The gel strength of the tablets produced in Comparative Example 2 and Examples 7-12 was evaluated. Specifically, following the disintegration test method described in the Seventeenth Edition of the Japanese Pharmacopoeia, water (900 mL) was used as the test solution. After placing the tablets into the disintegration test apparatus, the basket containing the tablets (with a mesh bottom) was moved up and down in the container of water to agitate. After 2 hours, the gelled tablets were removed, and the gel strength was measured using a texture analyzer (manufactured by Eikoh Seiki Co., Ltd.) to determine the force required to press down 0.5 mm with a 5 mm diameter probe. In addition, for Comparative Example 2, Examples 7 and 9, tests were also performed using 900 mL each of dissolution test solution 1 (pH 1.2), Mc. Ilvain buffer solution (pH 4.0), and dissolution test solution 2 (pH 6.8) instead of distilled water.

[0067] (Pill disintegration time) The disintegration time of the tablets produced in Comparative Example 2 and Examples 7-12 was evaluated. Specifically, the disintegration time of the tablets was measured according to the disintegration test method described in the 17th edition of the Japanese Pharmacopoeia. Water (900 mL) was used as the test solution. After placing the tablets into the disintegration test apparatus, the basket containing the tablets (with a mesh bottom) was moved up and down in the container of water to agitate the contents. Measurement was continued until the sample in the test apparatus was no longer visible, and this time was defined as the disintegration time of the tablets.

[0068] (Dissolution properties of tablets) The disintegration time of the tablets produced in Comparative Example 2, Examples 7, 9, and 10 was evaluated. Specifically, the dissolution test of the tablets was performed according to the dissolution test method (Method 2) described in the Seventeenth Edition of the Japanese Pharmacopoeia, with the paddle rotation speed set to 50 rpm and pH 7.5 (900 mL) used as the test solution. The test solution was collected at 0, 30, 60, 180, 300, 420, 480, 540, and 720 minutes from the start of the test, and the drug concentration was measured using a spectrophotometer. The test was performed on 3 tablets for each example, and the average value of the dissolution rate was calculated.

[0069] [Comparative Example 1] A pharmaceutical composition was prepared by mixing 50 mg of mirabegron with 119.6 mg of polyethylene glycol (manufactured by Sanyo Chemical Industries, Ltd.).

[0070] [Example 1] A pharmaceutical composition was prepared in the same manner as in Comparative Example 1, except that polyethylene glycol was replaced with sodium benzoate (manufactured by Fushimi Pharmaceutical Co., Ltd.).

[0071] [Example 2] A pharmaceutical composition was prepared in the same manner as in Comparative Example 1, except that polyethylene glycol was replaced with trehalose (manufactured by Hayashibara Co., Ltd.).

[0072] [Example 3] A pharmaceutical composition was prepared in the same manner as in Comparative Example 1, except that polyethylene glycol was replaced with erythritol (manufactured by Bussan Food Science Co., Ltd.).

[0073] [Example 4] A pharmaceutical composition was prepared in the same manner as in Comparative Example 1, except that polyethylene glycol was replaced with maltitol (manufactured by Mitsubishi Corporation Life Sciences).

[0074] [Example 5] Tablets were manufactured using the same pharmaceutical composition as Comparative Example 1, except that polyethylene glycol was replaced with α-cyclodextrin (manufactured by Nippon Shokuhin Kako Co., Ltd.).

[0075] [Example 6] A pharmaceutical composition was prepared in the same manner as in Comparative Example 1, except that polyethylene glycol was replaced with aspartame (manufactured by Ajinomoto Co., Inc.).

[0076] [Result-1] Table 1 shows the results of stability tests conducted on the pharmaceutical compositions using mirabegron as the active ingredient, which were manufactured in Comparative Example 1 and Examples 1-6 above. In Table 1, "Initial" refers to the test results using the pharmaceutical composition immediately after manufacture, "Accelerated 2W Open" refers to the test results using the pharmaceutical composition left open for two weeks at 40°C and 75%RH, and "60°C 2W Sealed" refers to the test results using the pharmaceutical composition left sealed for two weeks at 60°C.

[0077] [Table 1]

[0078] Table 1 shows that the pharmaceutical compositions containing sodium benzoate, trehalose, erythritol, maltitol, α-cyclodextrin, and aspartame (Examples 1-6) significantly suppressed the generation of related substances compared to the pharmaceutical composition containing polyethylene glycol (Comparative Example 1). In other words, these hydrophilic bases were shown to contribute to the stabilization of mirabegron. Although Examples 1-6 are results for pharmaceutical compositions in which the active pharmaceutical ingredient mirabegron has not been formulated, similar results are expected when these are made into tablets.

[0079] [Comparative Example 2] 50 mg of mirabegron, 70 mg of polyethylene oxide (manufactured by Dow Chemical), 119.6 mg of polyethylene glycol, and 2.5 mg of magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.) were mixed together, and tablets were manufactured using a single-shot tablet press (manufactured by Ichihashi Seiki Co., Ltd.).

[0080] [Example 7] Tablets were manufactured in the same manner as in Comparative Example 2, except that polyethylene glycol was replaced with sodium benzoate.

[0081] [Example 8] Tablets were manufactured in the same manner as in Comparative Example 2, except that polyethylene glycol was replaced with trehalose.

[0082] [Example 9] Tablets were manufactured in the same manner as in Comparative Example 2, except that polyethylene glycol was replaced with erythritol.

[0083] [Example 10] Tablets were manufactured in the same manner as in Comparative Example 2, except that polyethylene glycol was replaced with maltitol.

[0084] [Example 11] Tablets were manufactured in the same manner as in Comparative Example 2, except that polyethylene glycol was replaced with α-cyclodextrin.

[0085] [Example 12] Tablets were manufactured in the same manner as in Comparative Example 2, except that polyethylene glycol was replaced with aspartame.

[0086] Table 2 shows the specific compositions of the tablets in Comparative Example 2 and Examples 7-12.

[0087] [Table 2]

[0088] [Result-2] The results of the tests performed on the tablets produced in Comparative Example 2 and Examples 7-12 are shown in Table 3 and Figure 1.

[0089] [Table 3]

[0090] Table 3 shows that the tablets containing sodium benzoate, trehalose, erythritol, maltitol, and α-cyclodextrin (Examples 7-11) exhibited gelation rates and / or gel strengths equivalent to or significantly superior to those of the tablet containing polyethylene glycol (Comparative Example 2). Furthermore, the tablets of Examples 7 and 9 demonstrated gelation rates and / or gel strengths equivalent to or better than those of the tablet of Comparative Example 2, even in low-pH solutions.

[0091] Furthermore, Table 3 shows that the tablets of Examples 7-12 have a longer disintegration time compared to the tablet of Comparative Example 2. Also, Figure 1 shows that the tablets of Examples 7 and 9 have superior dissolution properties compared to the tablet of Comparative Example 2.

[0092] The results above demonstrate that the tablets containing the specific hydrophilic bases of Examples 7 to 12 exhibited comparable or superior effects to the tablet of Comparative Example 2 in terms of sustained-release indicators such as gelation rate, gel strength, disintegration time, and dissolution. [Industrial applicability]

[0093] Because the stability of pharmaceutical compositions containing mirabegron or pharmaceutically acceptable salts thereof is improved, the present invention can be suitably used as a novel controlled-release pharmaceutical composition containing mirabegron or pharmaceutically acceptable salts thereof.

Claims

1. A controlled-release pharmaceutical composition comprising mirabegron or a pharmaceutically acceptable salt thereof, a hydrogel-forming polymer, and a hydrophilic base, The hydrophilic base consists of at least one selected from the group consisting of sodium benzoate, trehalose, erythritol, maltitol, α-cyclodextrin, and aspartame. The hydrophilic base is mixed with mirabegron, The hydrogel-forming polymer is one or more selected from the group consisting of polyethylene oxide and carboxyvinyl polymer. A controlled-release pharmaceutical composition.

2. The release-controlled pharmaceutical composition according to claim 1, wherein the content of the hydrophilic base is 4 to 49% by weight.

3. The release-controlled pharmaceutical composition according to claim 1 or 2, wherein the hydrogel-forming polymer is polyethylene oxide.

4. The release-controlled pharmaceutical composition according to any one of claims 1 to 3, wherein the content of the hydrogel-forming polymer is 28 to 74% by weight.

5. A controlled-release pharmaceutical composition according to any one of claims 1 to 4, which is in the form of a tablet.

6. The gelation rate in water is 55.0 to 85.0%, and / or the gel strength in water is 3.0 to 25.5 g: The gelation rate is a value calculated by performing an elution test using the test solution and following the calculation formula (1) below. Gelation rate (G, %) = (1 - (W) ｏｂｓ ) / (W ｉｎｉ )) × 100 ... (1) W ｏｂｓ : Weight of the portion that has not gelled after the start of the test W ｉｎｉ : Tablet weight before the start of the test The release-controlled pharmaceutical composition according to claim 5, wherein the gel strength is the force required to press down the release-controlled pharmaceutical composition, which has been gelled according to the disintegration test method described in the 17th edition of the Japanese Pharmacopoeia, by 0.5 mm with a 5 mm diameter probe, as measured by a texture analyzer.

7. A method for producing a controlled-release pharmaceutical composition, comprising the step of blending mirabegron or a pharmaceutically acceptable salt thereof, a hydrogel-forming polymer, and a hydrophilic base, The hydrophilic base consists of at least one selected from the group consisting of sodium benzoate, trehalose, erythritol, maltitol, α-cyclodextrin, and aspartame. The hydrophilic base is mixed with mirabegron, The hydrogel-forming polymer is one or more selected from the group consisting of polyethylene oxide and carboxyvinyl polymer. Manufacturing method.

Images