Sustained-release formulation

Abstract

To provide a mirabegron sustained-release formulation that has good sustained-release properties and allows for control of the sustained-release properties according to the purpose. [Solution] A sustained-release formulation containing mirabegron, polyethylene oxide with an average molecular weight of 1 to 8 million, and one or more water-conducting components selected from gum arabic powder, isomalt hydrate, polyvinyl alcohol-polyethylene glycol graft copolymer, pullulan, trehalose, erythritol, xanthan gum, hydroxypropyl cellulose, DL-malic acid, sodium hydrogen phosphate hydrate, and sodium dihydrogen phosphate hydrate.

Description

Technical Field

[0001] The present invention relates to a sustained-release tablet containing mirabegron and a method for producing the same.

Background Art

[0002] Mirabegron (chemical name: 2-(2-amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide) and its pharmaceutically acceptable salts are marketed under the name "Betanis (registered trademark) tablets" (hereinafter referred to as "pre-approved preparations") as therapeutic agents for overactive bladder with selective β3-adrenergic receptor agonism.

[0003] Overactive bladder (OAB) is one of the lower urinary tract symptoms (urinary disorders), which is the symptom of urgent urinary urge and frequent urination resulting from sudden involuntary contractions of the bladder, and may be accompanied by nocturia and urge incontinence. Overactive bladder is roughly classified into two types of etiologies: neurogenic and non-neurogenic. Frequent urination is defined as "urination frequency of 7-8 times or more during the day and 2 times or more at night", and urinary incontinence is defined as "a state where involuntary or unconscious urine leakage becomes a social and hygienic problem". Due to frequent urination and urinary incontinence, etc., it significantly reduces the quality of life (QOL), and burdens not only the patients themselves but also their surrounding family members and caregivers. In Japan, it is estimated that 12.4% (8.1 million people) of the population aged 40 and over are overactive bladder patients.

[0004] Since overactive bladder is considered to be caused by a potential state of overactive detrusor muscle, muscarinic receptor antagonists having mainly a bladder contraction inhibitory action have been widely used for the treatment of overactive bladder. However, since they are accompanied by side effects such as dysuria, increased residual urine volume, and urinary retention, mirabegron, a selective β3-adrenergic receptor agonist with reduced side effects, has been developed. In addition, for the treatment of overactive bladder, it is necessary to exert a constant effect and limit side effects. Therefore, sustained-release preparations have been developed to maintain a constant blood concentration of mirabegron.

[0005] As a mirabegron sustained-release formulation, a sustained-release formulation has been proposed that consists of a hydrogel-forming polymer such as polyethylene oxide and a hydrophilic additive such as polyethylene glycol to allow water to penetrate the formulation, thereby gradually releasing the drug without excessive release as it moves through the gastrointestinal tract by guiding water into the hydrogel with the hydrophilic additive (Patent Document 1, Non-Patent Document 1). Furthermore, for the purpose of improving stability, a release-controlled pharmaceutical composition containing a hydrogel-forming polymer such as polyethylene oxide and a hydrophilic base such as erythritol has been disclosed (Patent Document 2). In addition, for the purpose of suppressing discoloration and swelling, a sustained-release tablet containing polyethylene oxide and a hydrophilic additive such as hypromellose or hydroxypropylcellulose has been disclosed (Patent Document 3). [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] International Publication No. 2010 / 038690 [Patent Document 2] Japanese Patent Publication No. 2023-066053 [Patent Document 3] Japanese Patent Publication No. 2023-143873 [Non-patent literature]

[0007] [Non-Patent Document 1] Kondo et al., Drug Delivery System 210-218, 31-3, 2016. [Overview of the project] [Problems that the invention aims to solve]

[0008] The present invention aims to provide a mirabegron sustained-release formulation that exhibits good sustained-release properties, allows for controllable sustained-release properties according to the purpose, and has excellent stability, as well as a method for producing the sustained-release formulation. [Means for solving the problem]

[0009] As a result of investigations to solve the above problems, the present inventors have found a method for producing a sustained-release formulation containing a specific polyethylene oxide and a water-conducting component that exhibits the same dissolution behavior as an approved formulation, i.e., has bioequivalence, has excellent stability of mirabegron, and can be easily produced using conventional pharmaceutical manufacturing equipment. In other words, the present invention relates to the following 1) to 2). 1) A sustained-release formulation containing mirabegron, polyethylene oxide with an average molecular weight of 1 to 8 million, and one or more water-conducting components selected from gum arabic powder, isomalt hydrate, polyvinyl alcohol-polyethylene glycol graft copolymer, pullulan, trehalose, erythritol, xanthan gum, hydroxypropyl cellulose, DL-malic acid, sodium hydrogen phosphate hydrate, and sodium dihydrogen phosphate hydrate. 2) A method for producing a mirabegron sustained-release formulation, comprising: a) granulating mirabegron, polyethylene oxide with an average molecular weight of 1 to 8 million, and one or more water-conducting components selected from gum arabic powder, isomalt hydrate, polyvinyl alcohol-polyethylene glycol graft copolymer, pullulan, trehalose, erythritol, xanthan gum, hydroxypropyl cellulose, DL-malic acid, sodium hydrogen phosphate hydrate, and sodium dihydrogen phosphate hydrate to obtain granules; b) mixing the granules, an antioxidant, and a lubricant to obtain a tablet powder; c) compressing the tablet powder to obtain a plain tablet; and d) film coating the plain tablet to obtain a film-coated tablet. [Effects of the Invention]

[0010] The sustained-release formulation of the present invention contains mirabegron, a specific polyethylene oxide, and a water-conducting component, exhibits good sustained-release properties, and allows for control of the sustained-release properties according to the purpose. It also has excellent stability of mirabegron and can be easily manufactured using conventional pharmaceutical manufacturing equipment in processes such as granulation, mixing, and tableting. [Modes for carrying out the invention]

[0011] The sustained-release formulation of the present invention exhibits good sustained-release properties and allows for control of the sustained-release properties according to the purpose. For example, it may have dissolution behavior similar to that of an approved formulation and may be a bioequivalent formulation. Specifically, the mirabegron sustained-release formulation of the present invention has an elution rate of 10-30% by mass at 60 minutes and 20-50% by mass at 120 minutes under the condition of a single-solution paddle at 50 rpm. Under the condition of a water paddle at 50 rpm, the elution rate is 15-55% by mass at 300 minutes, 35-65% by mass at 420 minutes, and 70-95% by mass at 720 minutes. Under the condition of a pH 7.5 paddle at 200 rpm, the elution rate is 15-55% by mass at 120 minutes, 35-65% by mass at 180 minutes, and 70-95% by mass at 300 minutes. The preferred elution behavior is an elution rate of 10-30% by mass at 60 minutes and 20-50% by mass at 120 minutes under the condition of a single-solution paddle at 50 rpm. Under conditions of a water paddle at 50 rpm, the elution rate is 18-52% by mass at 300 minutes, 30-62% by mass at 420 minutes, and 65-100% by mass at 720 minutes. Under conditions of pH 7.5 paddle at 200 rpm, the elution rate is 18-60% by mass at 120 minutes, 38-62% by mass at 180 minutes, and 75-100% by mass at 240 minutes.

[0012] The sustained-release formulation of the present invention contains mirabegron, a specific polyethylene oxide, and a water-conducting component. Furthermore, the mirabegron sustained-release formulation of the present invention is in a state in which mirabegron, polyethylene oxide, and the water-conducting component are uniformly dispersed and mixed. Unless otherwise specified in the present invention, the use of each pharmaceutical additive is as defined in the Pharmaceutical Additives Dictionary.

[0013] As the mirabegron of the present invention, mirabegron or a pharmaceutically acceptable salt thereof can be used. Examples of pharmaceutically acceptable acids for mirabegron include mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphates; and organic acids such as acetic acid, oxalic acid, maleic acid, fumaric acid, citric acid, benzoic acid, methanesulfonic acid, propionic acid, lactic acid, malic acid, tartaric acid, carbonic acid, picric acid, formic acid, and ethanesulfonic acid.

[0014] The particle size of mirabegron may be within a range that is easy to elute and easy to manufacture in terms of formulation. For example, the average particle size (d50) is preferably 1 to 30 μm, more preferably 3 to 20 μm, and even more preferably 5 to 15 μm. The particle size is based on the volume-based particle size distribution measured using a laser diffraction / scattering particle size distribution measuring device. Examples of the laser diffraction / scattering particle size distribution measuring device include DMS2 Ver11.1.0-257F2 of Microtrac Bell Co., Ltd.

[0015] In the case of the free form of mirabegron, either the α-form or the β-form of the crystal form may be used, and from the viewpoint of stability, it is preferable to use the α-form.

[0016] The content of mirabegron in the sustained-release formulation of the present invention is, based on the mass of the formulation, in terms of the free form of mirabegron, for example, 5 to 30% by mass, preferably 8 to 25% by mass. Also, suitable contents of mirabegron in the sustained-release formulation (tablet) include 25 mg or 50 mg.

[0017] Polyethylene oxide is a base component constituting a hydrogel in the presence of moisture and is a linear polymer obtained by polymerization of ethylene glycol. However, as the polyethylene oxide of the present invention, a molecular weight that becomes a hydrogel and that is not rapidly dissolved in the digestive tract but is such that almost all finally dissolves is used. The average molecular weight of polyethylene oxide is 1 million to 8 million, preferably 1 million to 4 million, more preferably 1.5 million to 3 million, and even more preferably 2 million ± 500,000. In the present invention, the average molecular weight refers to the average molecular weight expressed as the number average molecular weight unless otherwise specified. The viscosity of the polyethylene oxide is, for example, the viscosity of a 5% aqueous solution at 25°C is 12 mPa·s or more, preferably, the viscosity of a 5% aqueous solution at 25°C is 12 mPa·s or more and the viscosity of a 1% aqueous solution at 25°C is 40000 mPa·s or less, more preferably, the viscosity of a 2% aqueous solution at 25°C is 400 mPa·s or more and the viscosity of a 1% aqueous solution at 25°C is 7500 mPa·s or less, still more preferably, the viscosity of a 2% aqueous solution at 25°C is 400 mPa·s or more and the viscosity of a 1% aqueous solution at 25°C is 5500 mPa·s or less, and most preferably, the viscosity of a 2% aqueous solution at 25°C is 2000 - 4000 mPa·s.

[0018] Examples of such polyethylene oxides include polyethylene oxide 7000K, polyethylene oxide 5000K, trade name Polyox WSR-308 [number average molecular weight: 8 million, viscosity: 10000 - 15000 mPa·s (1% aqueous solution at 25°C)], Polyox WSR-303 [number average molecular weight: 7 million, viscosity: 7500 - 10000 mPa·s (1% aqueous solution at 25°C)], Polyox WSR Coagulant [number average molecular weight: 5 million, viscosity: 5500 - 7500 mPa·s (1% aqueous solution at 25°C)], Polyox WSR-301 [number average molecular weight: 4 million, viscosity: 1650 - 5500 mPa·s (1% aqueous solution at 25°C)], Polyox WSR-N-60K [number average molecular weight: 2 million, viscosity: 2000 - 4000 mPa·s (2% aqueous solution at 25°C)], Polyox WSR-N-12K [number average molecular weight: 1 million, viscosity: 400 - 800 mPa·s (2% aqueous solution at 25°C)], and the like.

[0019] The particle size of the polyethylene oxide of the present invention has no particular influence on the sustained release property, but from the ease of manufacturing the sustained release preparation and the ease of granulation, those having an average particle size of 75 - 840 μm are preferred, and those having an average particle size of 75 - 149 μm are more preferred.

[0020] The polyethylene oxide content in the sustained-release formulation of the present invention is preferably 10 to 80% by mass, more preferably 15 to 70% by mass, even more preferably 20 to 60% by mass, and still more preferably 20 to 35% by mass, based on the mass of the formulation. Excellent sustained-release properties are exhibited when the polyethylene oxide content is within the above range.

[0021] To adjust the sustained release properties of the sustained-release formulation of the present invention, polyethylene oxide with an average molecular weight of 900,000 or less, which is different from the polyethylene oxide with an average molecular weight of 1 to 8 million, hydrogel-forming polymer substances other than polyethylene oxide, sodium chloride, sodium acetate, magnesium aluminometasilicate, hypromellose, etc. may be added to the formulation as a sustained-release modifier. Here, adjusting the sustained release properties means increasing or decreasing the slope of the line (dissolution rate) in dissolution tests with various eluents, where dissolution occurs almost linearly from 0 hours to the time when the dissolution rate reaches 85% most recently, in order to bring it closer to the dissolution rate of the approved formulation.

[0022] Examples of polyethylene oxides with an average molecular weight of 900,000 or less include those with an average molecular weight of 600,000 or less, more preferably 400,000 or less, even more preferably 200,000 or less, preferably 20,000 or more, more preferably 80,000 or more, and even more preferably 100,000 or more. These polyethylene oxides with average molecular weights can be used individually or in combination of two or more. When using a single polyethylene oxide, one with an average molecular weight of 600,000 or 200,000 can be used. The release rate can be suppressed by adding polyethylene oxides with such molecular weights. Examples of polyethylene oxides with an average molecular weight of 900,000 or less include polyethylene oxide 200K, and commercially available products such as Polyox WSR-1105 [number average molecular weight: 900,000, viscosity: 8800-17600 mPa·s (5% aqueous solution 25℃)], Polyox WSR-205 [number average molecular weight: 600,000, viscosity: 4500-8800 mPa·s (5% aqueous solution 25℃)], Polyox WSR N-3000 [number average molecular weight: 400,000, viscosity: 2250-4500 mPa·s (5% aqueous solution 25℃)], Polyox WSR-N-750 [number average molecular weight: 300,000, viscosity: 600-1200 mPa·s (5% aqueous solution 25℃)], Polyox WSR-N-80 [number average molecular weight: 200,000, viscosity: 55-90 mPa·s (5% aqueous solution 25℃)], 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).

[0023] Therefore, in the sustained-release formulation of the present invention, it is preferable to use a combination of polyethylene oxide having an average molecular weight of 2 million and a viscosity of 2000-4000 mPa·s (2% aqueous solution at 25°C) and polyethylene oxide having an average molecular weight of 600,000 or less, for example, polyethylene oxide having an average molecular weight of 600,000 and a viscosity of 4500-8800 mPa·s (5% aqueous solution at 25°C), or polyethylene oxide having an average molecular weight of 200,000 and a viscosity of 55-90 mPa·s (5% aqueous solution at 25°C).

[0024] Other hydrogel-forming polymers include hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, carboxyvinyl polymer, and macrogol. Examples of macrogol include macrogol 20000 or macrogol 35000.

[0025] The amount (by mass) of the above-mentioned sustained-release regulator is 100:5 to 100:35, preferably 100:10 to 100:30, relative to polyethylene oxide with an average molecular weight of 1 to 8 million.

[0026] The water-conducting component of the present invention is a component that guides water into a composition in which polyethylene oxide and mirabegron with an average molecular weight of 1 to 8 million are uniformly mixed, and when it comes into contact with water, it forms a hydrogel not only on the outside but also inside the composition. Examples of water-conducting functions include polymer gels that partially dissolve and swell in water to form a water-soluble gel and guide water into the interior, porous materials that are insoluble but guide water through pores, and soluble materials that dissolve in water and create voids in the composition to guide water.

[0027] Examples of such water-conducting components include: acacia powder, isomalt hydrate, polyvinyl alcohol / polyethylene glycol graft copolymer (Colicoat® IR), pullulan, acacia powder, isomalt hydrate, polyvinyl alcohol / polyethylene glycol graft copolymer, pullulan, trehalose, erythritol, xanthan gum, hydroxypropyl cellulose, DL-malic acid, sodium hydrogen phosphate hydrate, sodium dihydrogen phosphate hydrate, carboxymethyl ether, propylene glycol ester, and locust bean. Gum, galactomannan, alginic acid derivatives, carrageenan, tragacanth gum, acacia gum, karaya gum, chitin, chitosan, mucopolysaccharides, konjac, British gum, dextran, substituted starch, scleroglucan, methylcellulose, amylose, pectin, pregelatinized starch, hydroxypropyl starch, croscarmellose sodium, sodium starch glycolate, calcium lactate, calcium gluconate, sodium saccharin hydrate, potassium sorbate, sucralose, anhydrous sodium sulfate, anhydrous monohydrogen phosphate, meta Sodium phosphate, sodium lauryl sulfate, sodium benzoate, maltitol, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, aspartame, hypromellose, hydroxyethylcellulose, sodium carmellose, polyvinyl alcohol, copolyvidone, carmellose, anhydrous calcium hydrogen phosphate, magnesium aluminometasilicate, magnesium aluminosilicate, calcium silicate, porous silicon dioxide, erythritol, sodium stearyl fumarate, L-glutamic acid, L-arginine, corn Examples of other materials include rocoside starch, dextrin, ascorbic acid, sodium ascorbate, sodium chloride, potassium chloride, as well as carboxyvinyl polymers, chitosans, mannans, galactomannans, xanthan gums, carrageenans, acrylates, aminoalkyl methacrylate copolymers, methacrylate copolymers, polyacid anhydrides, polyamino acids, poly(methyl vinyl ether / maleic anhydride) polymers, glucans, etc. However, in the present invention, gum arabic powder, isomalt hydrate,It is one or more selected from polyvinyl alcohol-polyethylene glycol graft copolymer, pullulan, trehalose, erythritol, xanthan gum, hydroxypropyl cellulose, DL-malic acid, sodium hydrogen phosphate hydrate, and sodium dihydrogen phosphate hydrate, preferably one or more selected from gum arabic powder, isomalt hydrate, polyvinyl alcohol-polyethylene glycol graft copolymer, and pullulan.

[0028] The content of the water-conducting component is not particularly limited as long as it can control the release of mirabegron to an extent that is not affected by diet. For example, it is 5 to 80% by mass, preferably 10 to 70% by mass, more preferably 20 to 70% by mass, and even more preferably 40 to 65% by mass in the formulation.

[0029] The sustained-release formulation of the present invention is a composition in which mirabegron, polyethylene oxide with an average molecular weight of 1 to 8 million, and a water-conducting component are uniformly mixed. It can be manufactured by mixing and / or granulating and molding mirabegron, polyethylene oxide with an average molecular weight of 1 to 8 million, and the water-conducting component. Granulation is preferred in terms of content uniformity and tabletability. Here, mixing, granulation, and molding can be carried out according to conventional methods in the pharmaceutical technology field. In addition, during the above mixing, granulation, and / or molding, the following other pharmacokinetically acceptable pharmaceutical additives can be used as desired.

[0030] To ensure uniformity in tablet quality, including content uniformity, hardness, and thickness, the granules preferably contain mirabegron, polyethylene oxide with an average molecular weight of 1 to 8 million, a water-conducting component, and, if necessary, a sustained-release regulator. The granules preferably contain a binder to bind the components together and form particles. The size of the granules is 50 to 200 μm, as the D50 of the particle size distribution.

[0031] In addition to the above-mentioned components, the sustained-release formulation of the present invention may optionally contain other pharmaceutically acceptable pharmaceutical additives. Examples of other pharmaceutical additives include excipients, lubricants, binders, and disintegrants. Furthermore, if necessary, formulation additives such as antioxidants, film coating agents, colorants, light-shielding agents, and sweeteners may also be used.

[0032] Examples of binders include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone, with hydroxypropylcellulose and hydroxypropylmethylcellulose being preferred.

[0033] Examples of lubricants include magnesium stearate, calcium stearate, talc, and colloidal silica.

[0034] Examples of disintegrants include lactose, sucrose, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, and low-substituted hydroxypropylcellulose.

[0035] Examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, dextrin, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminometasilicate.

[0036] As antioxidants, those that do not affect the elution behavior can be used. Examples include dibutylhydroxytoluene, propyl gallate, butylhydroxyanisole, ascorbic acid, sodium ascorbate, erythorbic acid, sodium nitrite, sodium bisulfite, sodium pyrosulfite, citric acid, and sodium edetate. Preferably, dibutylhydroxytoluene, propyl gallate, and sodium ascorbate are used, and more preferably, dibutylhydroxytoluene. These antioxidants are expected to suppress the products of each component of the sustained-release formulation of the present invention, such as polyethylene oxide, produced by oxidizing components such as oxygen.

[0037] Examples of colorants include Food Blue No. 1, Food Blue No. 2, Food Yellow No. 4, Food Red No. 2, Food Red No. 3, Food Blue No. 1 aluminum lake, Food Blue No. 2 aluminum lake, Food Red No. 2 aluminum lake, iron(III) oxide (red), titanium dioxide, yellow iron(III) oxide, caramel, and talc. These colorants are expected to suppress the decomposition of mirabegron by light.

[0038] Examples of light-shielding agents include titanium dioxide, calcium carbonate, zinc oxide, talc, iron oxides such as yellow iron(III) oxide, iron(III) oxide, and black iron oxide, as well as food coloring Yellow No. 5 and food coloring Red No. 102, with titanium dioxide and calcium carbonate being preferred. These light-shielding agents are expected to suppress the decomposition of mirabegron by light.

[0039] Examples of sweeteners include sodium saccharin, dipotassium glycyrrhizinate, aspartame, and stevia.

[0040] Other pharmaceutical additives may be used individually or in combination of two or more as appropriate. The amounts used can be appropriate; for example, antioxidants may be present in amounts of 0.025% to 0.25% by mass of the formulation, and stabilizers in amounts of 0.05% to 1% by mass of the formulation. Among pharmaceutical excipients, macrogol, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hypromellose, lactose, and mannitol are expected to suppress mirabegron-related substances in the formulation.

[0041] The resulting uncoated tablets may be film-coated. Film coating can typically be done using film coating agents and their additives commonly used in pharmaceutical formulations. Here, the film coating agent is not particularly limited, but examples include cellulosic film coating agents such as carmellose, carmellose sodium, carmellose calcium, hydroxypropylcellulose, hypromellose, hydroxyethylcellulose, hydroxymethylcellulose, methylcellulose, and carboxymethylcellulose, as well as acacia powder, gelatin pullulan, dextrin, carboxymethyl starch sodium, sodium alginate, polyvinylpyrrolidone, and polyvinyl alcohol. Cellulosic film coating agents are preferred, and hypromellose is more preferred.

[0042] The plasticizer is not particularly limited, but examples include polyethylene glycol (e.g., polyethylene glycol 400, polyethylene glycol 4000, polyethylene glycol 6000, etc.), triethyl citrate, glycerin, castor oil, polyoxyethylene hydrogenated castor oil, polysorbate 80, lauromacrogol, triacetin, etc., with polyethylene glycol or triacetin being preferred.

[0043] The lubricant for film coating is not particularly limited, but examples include talc, hydrated silicon dioxide, light anhydrous silicic acid, magnesium aluminometasilicate, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, stearic acid, calcium stearate, and magnesium stearate, with talc being preferred.

[0044] Examples of dyes for film coating include those described above as colorants and / or light-shielding agents, preferably yellow ferric oxide, ferric oxide, or titanium dioxide.

[0045] Examples of solvents for dissolving / suspending film coating agents include alcohols such as methanol, ethanol, and isopropyl alcohol, acetone, toluene, hexane, methyl ethyl ketone, and water, or mixtures thereof. Ethanol and water are preferred, and water is more preferred.

[0046] In the film-coated tablets, there are no clear limitations on the amount of film coating, but for example, a 250 mg / tablet uncoated tablet is preferably coated with 2 to 20 mg / tablet, more preferably with 4 to 12 mg / tablet, and a 125 mg / tablet uncoated tablet is preferably coated with 1 to 10 mg / tablet, more preferably with 2 to 8 mg / tablet.

[0047] The sustained-release tablets of the present invention mainly contain polyethylene oxide with an average molecular weight of 10 to 8 million as a hydrophilic component and a water-conducting component. Therefore, the moisture content is preferably 0.01 to 10% by mass, more preferably 0.1 to 7% by mass, and more preferably 0.5 to 5% by mass, relative to the total weight of the tablet. Moisture content can be measured using an infrared moisture meter (FD-660, manufactured by Kett Scientific Research Institute) at 110°C for 15 minutes.

[0048] As described above, in order to suppress moisture absorption, the sustained-release tablets of the present invention can use polychlorotrifluoroethylene copolymer, cycloolefin copolymer, polychlorotetrafluoroethylene, vinylidene chloride, etc. as primary packaging materials, and it is preferable to further package the temporarily packaged tablets in aluminum film / polyethylene pillow packaging.

[0049] The following describes the manufacturing method for the sustained-release formulation of the present invention, but these descriptions are not intended to limit the present invention. The sustained-release formulation of the present invention can be manufactured by, for example, one or more steps selected from crushing, granulation, mixing, sizing, tableting, film coating, etc., in accordance with conventional methods in the field of pharmaceutical manufacturing. For example, it can be manufactured by the following steps a) to d). a) A process of granulating mirabegron, polyethylene oxide with an average molecular weight of 1 to 8 million, and one or more water-conducting components selected from gum arabic powder, isomalt hydrate, polyvinyl alcohol-polyethylene glycol graft copolymer, pullulan, trehalose, erythritol, xanthan gum, hydroxypropyl cellulose, DL-malic acid, sodium hydrogen phosphate hydrate, and sodium dihydrogen phosphate hydrate to obtain granules. b) A step of mixing the granules, antioxidant and lubricant to obtain a tablet powder, c) A step of compressing the tablet powder to obtain a tablet, d) A step of obtaining a film-coated tablet by film coating the plain tablet.

[0050] Mirabegron, polyethylene oxide with an average molecular weight of 1 to 8 million, and water-conducting components can be crushed or pulverized to achieve the desired particle size. Conventional crushing and pulverizing methods can be employed. Examples include impact pulverizers, wet / dry granulators, crushing granulators, and air-jet pulverizers.

[0051] Granulation can be carried out using conventional granulation methods. Examples include fluidized bed granulation, agitation granulation, rolling fluidized bed granulation, extrusion granulation, melt granulation, and dry granulation. Examples of granulation equipment include fluidized bed granulators, granulation coating equipment equipped with a horizontal rotating disc having a smooth contact surface, granulation coating equipment with a rotating disc having a ventilation section and a smooth surface located at the bottom of the fluidized bed, and dry granulation equipment that compresses, molds, crushes, and granulates the raw material powder. Wet granulation is preferred because it has little effect on dissolution and drying of the solvent, such as water, and has a high solvent removal rate. Furthermore, fluidized bed granulation is suitable because drying can be carried out immediately afterward.

[0052] When granulating using dry granulation, for example, the material can be compressed and molded in a dry granulator along with additives such as mirabegron, polyethylene oxide, water-permeable components, and lubricants, and then coarsely crushed and sized to obtain granules of the desired size.

[0053] When granulating by wet granulation, for example, in fluidized bed granulation, the mirabegron, polyethylene oxide with an average molecular weight of 1 to 8 million, water-conducting components, and additives such as excipients can be fluidized while spraying the required amount of liquid or water containing the water-conducting components and / or binders. The liquid containing the water-conducting components is prepared by dissolving or dispersing essential components in a solvent such as water, ethanol, or methanol. Of the solvents, ethanol and methanol dissolve mirabegron to some extent, which can easily affect the solubility and stability of the active drug, so water is preferred. It is also possible to use a mixture of these solvents as appropriate. In stirred granulation, mirabegron, polyethylene oxide with an average molecular weight of 1 to 8 million, water-conducting components, and other pharmaceutical additives are stirred while adding a liquid containing a binder, followed by drying.

[0054] The amount of water used during granulation is not particularly limited, as long as it is sufficient to uniformly dissolve or suspend (disperse) the binder and / or other pharmaceutical additives. When the water-conducting component is used in a solid state, the amount is not particularly limited, as long as it is sufficient to granulate polyethylene oxide with an average molecular weight of 1 to 8 million. The amount added is usually 100 to 300% by mass relative to the polyethylene oxide. The rate at which water is added during granulation is not particularly limited, as long as it does not result in an uneven mixture consisting of powdery aggregates and untreated powder.

[0055] The solid content concentration of the binder solution used during granulation is, for example, 1 to 20% by mass as a formulation amount. There are no particular restrictions as long as it is pharmaceutically acceptable. The binder may be introduced into the granulator in its solid state and water may be sprayed as the binder solution, or it may be dissolved and then sprayed as the binder solution.

[0056] After wet granulation, drying can be performed, and the subsequent drying process can be carried out using drying methods commonly used in the field of pharmaceutical manufacturing. Examples of methods that dry the granules include fluidized bed granulators, shelf dryers, and vacuum dryers. After granulation, it is preferable to adjust the particle size of the granules by sizing, crushing, and sieving, with the particle size of the granules being 1 mm or less, preferably 0.8 mm or less, relative to the mesh diameter through which they pass. Sizing, crushing, and sieving can be performed using equipment commonly used in the pharmaceutical manufacturing process, such as a Co-Mill.

[0057] Other pharmaceutical additives may be added or mixed as needed during or after granulation. Components added during granulation include binders, excipients, and disintegrants. When other pharmaceutical additives are added and mixed after granulation (also known as "post-addition"), excipients, disintegrants, antioxidants, and lubricants may be mixed.

[0058] Tableting methods include direct tableting, in which mirabegron, a water-conducting component, polyethylene oxide with an average molecular weight of 1 to 8 million, and an appropriate additive are mixed and then compressed to obtain tablets; wet granulation, in which mirabegron, a water-conducting component, polyethylene oxide with an average molecular weight of 1 to 8 million, and an additive are mixed and then granulated by spraying a binder solution; and melt granulation, in which mirabegron, a water-conducting component, polyethylene oxide with an average molecular weight of 1 to 8 million, and an appropriate low-melting-point substance are mixed, heated, and then granulated before tableting. Examples of tablet presses include rotary tablet presses and single-shot tablet presses, but the device is not particularly limited as long as it is a method by which a compressed product (preferably a tablet) is manufactured in a pharmaceutical manner.

[0059] After tableting, a film coating may be applied using a pan coating machine, for example, at a rate of 1% to 5% by mass per tablet. Film coating can be carried out in accordance with conventional methods of pharmaceutical manufacturing. [Examples]

[0060] (Example 1) 50 parts by mass of mirabegron, 70 parts by mass of polyethylene oxide (manufactured by Dow Chemical, trade name Polyox WSR N-60K (number average molecular weight: 2 million), the same applies hereafter unless otherwise specified), 127.1 parts by mass of gum arabic powder (manufactured by Fujifilm Wako Pure Chemical Industries, the same applies hereafter), 0.4 parts by mass of dibutylhydroxytoluene, and 2.5 parts by mass of magnesium stearate were mixed in a mortar to prepare a tablet powder. Using an oval 12.0 × 6.0 punch, the powder was compressed to a set hardness of 80N to obtain 250 mg sustained-release tablets containing 50 mg of mirabegron.

[0061] (Examples 2-4) Except for replacing the water-conducting component, gum arabic powder, with the components shown in Table 1, a 250 mg sustained-release tablet containing 50 mg of mirabegron was obtained using the same method as in Example 1.

[0062] [Table 1]

[0063] (Reference example 1) I used Betanis® 50mg tablets.

[0064] (Comparative Example 1) 50 parts by mass of mirabegron, 70 parts by mass of polyethylene oxide (product name Polyox WSR N-60K), 127.1 parts by mass of sucrose fatty acid ester (manufactured by Mitsubishi Chemical Corporation, Ryoto® Sugar Ester S-1670), 0.4 parts by mass of dibutylhydroxytoluene, and 2.5 parts by mass of magnesium stearate were mixed in a mortar to prepare a tablet powder. Using an oval 12.0 × 6.0 punch, the powder was compressed to a set hardness of 80N to obtain 250 mg sustained-release tablets containing 50 mg of mirabegron.

[0065] (Leaching test) In Examples 1 and 2, Reference Example 1, and Comparative Example 1, the dissolution behavior was measured under three conditions based on the dissolution test of the Japanese Pharmacopoeia: (1) one solution, paddle 50 rpm, (2) water, paddle 50 rpm, and (3) pH 7.5, paddle 200 rpm. Comparative Example 1 did not show similar dissolution behavior to Reference Example 1 under condition (2) water, paddle 50 rpm, so the dissolution test under condition (3) pH 7.5, paddle 200 rpm was omitted.

[0066] [Table 2]

[0067] [Table 3]

[0068] [Table 4]

[0069] In dissolution tests modeling the human stomach (Solution 1 (pH 1.2), paddle 50 rpm), the sustained-release formulations of Examples 1 and 2 showed suppressed excessive release of mirabegron. In dissolution tests modeling the small intestine (pH 7.5, paddle 200 rpm), the sustained-release formulations of Examples 1 and 2 of the present invention released sufficient mirabegron. In the dissolution test showing the greatest difference in the dissolution behavior of the formulations (water, paddle 50 rpm), the dissolution of the sustained-release formulation of Comparative Example 1 was insufficient. The dissolution behavior of the sustained-release formulations of Examples 1 and 2 and the target sustained-release formulation of Reference Example 1 were similar, with an f² function score of 42 or higher. The sustained-release formulations of Examples 1 and 2 of the present invention exhibit sufficient dissolution under various conditions, and their dissolution behavior is similar to that of the sustained-release formulation of Reference Example 1.

[0070] (Example 5) 50 parts by mass of mirabegron, 60 parts by mass of polyethylene oxide (molecular weight 2,000,000, manufactured by Dow Chemical, trade name Polyox WSR N-60K), 10 parts by mass of polyethylene oxide (molecular weight 600,000, manufactured by Dow Chemical, trade name WSR 205), and 119.6 parts by mass of gum arabic powder (manufactured by Sanei Pharmaceutical Trading Co., Ltd., Arabiccol JPF) were charged into a fluid bed granulator and granulated with purified water containing 7.5 parts by mass of hydroxypropyl cellulose to obtain sustained-release granules. 247.1 parts by mass of these sustained-release granules were mixed with 0.4 parts by mass of dibutylhydroxytoluene and 2.5 parts by mass of magnesium stearate. The mixture was then compressed using an oval 12.0 × 6.0 punch in a rotary tablet press at a rotation speed of 30 rpm and a set hardness of 120 N to obtain 250 mg uncoated tablets. In a coating apparatus, a coating solution equivalent to 5.2 parts by mass of hypromellose, 1.0 part by mass of polyethylene glycol, and 1.3 parts by mass of yellow ferric oxide was sprayed onto the uncoated tablet to obtain a film-coated sustained-release formulation (tablet) containing 50 mg of mirabegron, with each tablet weighing 257.5 mg.

[0071] (Example 6) 25 parts by mass of mirabegron, 60 parts by mass of polyethylene oxide (molecular weight 2,000,000, manufactured by Dow Chemical, trade name Polyox WSR N-60K), 10 parts by mass of polyethylene oxide (molecular weight 100,000, manufactured by Dow Chemical, trade name N10), and 144.6 parts by mass of gum arabic powder were charged into a fluid bed granulator and granulated with purified water containing 7.5 parts by mass of hydroxypropyl cellulose to obtain sustained-release granules. 247.1 parts by mass of these sustained-release granules were mixed with 0.4 parts by mass of dibutylhydroxytoluene and 2.5 parts by mass of magnesium stearate. The mixture was then compressed using an oval 12.0 × 6.0 punch in a rotary tablet press at a rotation speed of 30 rpm and a set hardness of 120 N to obtain 250 mg uncoated tablets. In a coating apparatus, a coating solution equivalent to 5.2 parts by mass of hypromellose, 1.0 part by mass of polyethylene glycol, 1.3 parts by mass of yellow ferric oxide, and 0.25 parts by mass of ferric oxide was sprayed onto the uncoated tablet to obtain a film-coated sustained-release formulation (tablet) containing 50 mg of mirabegron, with each tablet containing 257.5 mg.

[0072] (Example 7) 50 parts by mass of mirabegron, 60 parts by mass of polyethylene oxide (molecular weight 2,000,000, manufactured by Dow Chemical, trade name Polyox WSR N-60K), 10 parts by mass of polyethylene oxide (molecular weight 100,000, manufactured by Dow Chemical, trade name N10), and 119.6 parts by mass of isomalt hydrate (manufactured by BENEO, galenIQ801) were charged into a fluid bed granulator and granulated with purified water containing 7.5 parts by mass of hydroxypropyl cellulose to obtain sustained-release granules. 247.1 parts by mass of these sustained-release granules were mixed with 0.4 parts by mass of dibutylhydroxytoluene and 2.5 parts by mass of magnesium stearate. The mixture was then compressed using an oval 12.0 × 6.0 punch in a rotary tablet press at a rotation speed of 30 rpm and a set hardness of 120 N to obtain 250 mg uncoated tablets. In a coating apparatus, a coating solution equivalent to 5.2 parts by mass of hypromellose, 1.0 part by mass of polyethylene glycol, and 1.3 parts by mass of yellow ferric oxide was sprayed onto the uncoated tablet to obtain a film-coated sustained-release formulation (tablet) containing 50 mg of mirabegron, with each tablet weighing 257.5 mg. The moisture content of the tablets was 1.9%.

[0073] (Example 8) 25 parts by mass of mirabegron, 60 parts by mass of polyethylene oxide (molecular weight 2,000,000, manufactured by Dow Chemical, trade name Polyox WSR N-60K), 10 parts by mass of polyethylene oxide (molecular weight 100,000, manufactured by Dow Chemical, trade name N10), and 144.6 parts by mass of isomalt hydrate were charged into a fluid bed granulator and granulated with purified water containing 7.5 parts by mass of hydroxypropyl cellulose to obtain sustained-release granules. 247.1 parts by mass of these sustained-release granules were mixed with 0.4 parts by mass of dibutylhydroxytoluene and 2.5 parts by mass of magnesium stearate. The mixture was then compressed using an oval 12.0 × 6.0 punch in a rotary tablet press at a rotation speed of 30 rpm and a set hardness of 120 N to obtain 250 mg uncoated tablets. In a coating apparatus, a coating solution equivalent to 5.2 parts by mass of hypromellose, 1.0 part by mass of polyethylene glycol, 1.3 parts by mass of yellow ferric oxide, and 0.25 parts by mass of ferric oxide was sprayed onto the uncoated tablet to obtain a film-coated sustained-release formulation (tablet) containing 50 mg of mirabegron, with each tablet containing 257.5 mg.

[0074] (Leaching test) In Examples 5-7, Reference Example 1, and Comparative Example 1, the dissolution behavior was measured under three conditions based on the dissolution test of the Japanese Pharmacopoeia: (1) one solution, paddle 50 rpm, (2) water, paddle 50 rpm, and (3) pH 7.5, paddle 200 rpm. Comparative Example 1 did not show similar dissolution behavior to Reference Example 1 under condition (2) water, paddle 50 rpm, so the dissolution test under condition (3) pH 7.5, paddle 200 rpm was omitted.

[0075] [Table 5]

[0076] [Table 6]

[0077] [Table 7]

[0078] [Table 8]

[0079] The mirabegron sustained-release formulations of Examples 5 to 7 of the present invention exhibit equivalent dissolution properties in each eluate, reflecting the in vivo conditions, to Reference Example 1 of the previously approved formulation, and possess excellent sustained-release properties.

[0080] (Stability test) The samples were stored in a sealed container at a temperature of 40°C and a humidity of 75% RH, and the amount of related substances and elution tests were performed.

[0081] Method for measuring related substances: Add water / acetonitrile mixture (1:1) to one tablet of mirabegron 50 mg or one tablet of mirabegron 25 mg and stir to make exactly 50 mL and 25 mL, respectively. Filter these solutions through a membrane filter with a pore size of 0.45 μm or less. Remove the first 2 mL of filtrate and use the next filtrate as the sample solution. Accurately measure 1 mL of this solution and add water / acetonitrile mixture (1:1) to make exactly 100 mL to prepare the standard solution. Accurately take 10 μL each of the sample solution and standard solution and test them by liquid chromatography under the following conditions. Measure the peak area of ​​each solution using the automated integration method. Amount of related substances (%) = A T1 / A S Total amount of related substances (%) = A T2 / A S A T1 : Peak area of ​​each related substance obtained from the sample solution A T2 : The sum of the areas of each peak other than mirabegron obtained from the sample solution. A S Test conditions for the peak area of ​​mirabegron obtained from standard solutions Detector: UV absorbance spectrophotometer (measurement wavelength: 250 nm) Column: YMC-Triart C18 (4.6mm inner diameter x 150mm length, 3.5μm) Column temperature: Constant temperature around 40°C Sample temperature: 5℃ Mobile phase A: Mix 4.783 g of sodium dihydrogen phosphate dihydrate and 2.773 g of disodium hydrogen phosphate with water to make exactly 1000 mL of solution, and then mix with acetonitrile in an 8:2 ratio. Mobile phase B: Acetonitrile is used. Mobile phase delivery: The concentration gradient is controlled by changing the mixing ratio of mobile phase A and mobile phase B as follows. Flow rate: 1.0mL / min Area measurement range: Up to 90 minutes after injection

[0082] [Table 9]

[0083] [Table 10]

[0084] The mirabegron sustained-release formulations of Examples 5 and 7 of the present invention have a total relative content of 0.5% or less and exhibit superior stability compared to Reference Example 1 of the already approved formulation.

[0085] (Example of formulation 1) 50 parts by mass of mirabegron, 70 parts by mass of polyethylene oxide (molecular weight 2 million, manufactured by Dow Chemical, trade name Polyox WSR N-60K), and 119.6 parts by mass of gum arabic powder (manufactured by Sanei Pharmaceutical Trading Co., Ltd., Arabiccol JPF) were charged into a fluid bed granulator and granulated with purified water containing 7.5 parts by mass of hydroxypropyl cellulose to obtain sustained-release granules. 247.1 parts by mass of these sustained-release granules were mixed with 0.4 parts by mass of dibutylhydroxytoluene and 2.5 parts by mass of magnesium stearate. The mixture was then compressed using an oval 12.0 × 6.0 punch in a rotary tablet press at a rotation speed of 30 rpm and a set hardness of 80 N to obtain 250 mg uncoated tablets. In a coating apparatus, a coating solution equivalent to 5.2 parts by mass of hypromellose, 1.0 part by mass of polyethylene glycol, and 1.3 parts by mass of yellow ferric oxide was sprayed onto the uncoated tablet to obtain a film-coated sustained-release formulation (tablet) containing 50 mg of mirabegron, with each tablet weighing 257.5 mg.

[0086] (Formulation Examples 2-11) Except for replacing the gum arabic with the water-permeable component shown in Table 5, the same method as in Example 5 was used to produce a 250 mg sustained-release formulation (plain tablet) containing 50 mg of mirabellolon.

[0087] [Table 11]

[0088] (Formulation Example 12) 25 parts by mass of mirabegron, 55 parts by mass of polyethylene oxide (molecular weight 2 million, manufactured by Dow Chemical, trade name Polyox WSR N-60K), 15 parts by mass of polyethylene oxide 200K, and 144.6 parts by mass of isomalt hydrate were charged into a fluid bed granulator and granulated with purified water containing 7.5 parts by mass of hydroxypropyl cellulose. The mixture was then sieved through a φ0.8 mm sieve to obtain sustained-release granules with a particle size of 0.8 mm or less. 247.1 parts by mass of these sustained-release granules were mixed with 0.4 parts by mass of dibutylhydroxytoluene and 2.5 parts by mass of magnesium stearate. The mixture was then compressed using an oval 12.0 × 6.0 punch in a rotary tablet press at a rotation speed of 30 rpm and a set hardness of 120 N to obtain 250 mg uncoated tablets. In a coating apparatus, a coating solution equivalent to 5.2 parts by mass of hypromellose, 1.0 part by mass of polyethylene glycol, 1.3 parts by mass of yellow ferric oxide, and 0.25 parts by mass of ferric oxide was sprayed onto the uncoated tablet to obtain a film-coated sustained-release formulation (tablet) containing 50 mg of mirabegron, with each tablet containing 257.5 mg.

[0089] The mirabegron sustained-release tablets of the present invention satisfy the following conditions as a pharmaceutical formulation: (1) There are no tableting defects such as capping or sticking during tableting, and the content of the active ingredient is uniform. (2) It must have sufficient strength to prevent chipping or cracking during manufacturing or transportation. (3) There is no significant decrease in the dissolution properties of the mirabegron sustained-release tablets over time, and the dissolution properties remain similar to or equivalent to those at the initial stage. (4) The tablets weigh 650mg or less, making them relatively easy to swallow.

Claims

1. A sustained-release formulation containing mirabegron, polyethylene oxide with an average molecular weight of 1 to 8 million, and one or more water-conducting components selected from gum arabic powder, isomalt hydrate, polyvinyl alcohol / polyethylene glycol graft copolymer, pullulan, trehalose, erythritol, xanthan gum, hydroxypropyl cellulose, DL-malic acid, sodium hydrogen phosphate hydrate, and sodium dihydrogen phosphate hydrate.

2. The sustained-release formulation according to claim 1, wherein the water-conducting component is one or more selected from gum arabic powder, isomalt hydrate, polyvinyl alcohol / polyethylene glycol graft copolymer, and pullulan.

3. The sustained-release formulation according to claim 1, wherein the water-conducting component content is 5 to 80% by mass in the formulation.

4. The sustained-release formulation according to claim 1, wherein the water-conducting component content is 40 to 65% by mass in the formulation.

5. The sustained-release formulation according to claim 1, wherein the polyethylene oxide content with an average molecular weight of 100 to 800 million is 10 to 80% by mass in the formulation.

6. The sustained-release formulation according to claim 1, wherein the mirabegron content in the formulation is 25 mg or 50 mg.

7. Furthermore, the sustained-release formulation according to claim 1 contains one or more sustained-release regulators selected from polyethylene oxide with an average molecular weight of 900,000 or less, sodium chloride, sodium acetate, and magnesium aluminometasilicate hypromellose.

8. The sustained-release formulation according to claim 1, comprising mirabegron, polyethylene oxide, and a water-conducting component as granulated particles with a particle size of 1 mm or less.

9. The sustained-release formulation according to claim 1, wherein the dissolution rate of mirabegron satisfies the following three dissolution conditions. (1) Under the condition of a single-liquid paddle at 50 rpm, the concentration was 10-30% after 60 minutes and 20-50% after 120 minutes. (2) Under the condition of a water paddle at 50 rpm, the percentage was 30-62% after 420 minutes and 65-100% after 720 minutes. (3) Under conditions of pH 7.5 and a paddle at 200 rpm, the levels were 18-60% after 120 minutes and 75-100% after 240 minutes.

10. The sustained-release formulation according to claim 1, comprising one or more antioxidants selected from dibutylhydroxytoluene, propyl gallate, and sodium ascorbate.

11. The sustained-release formulation according to claim 1, comprising one or more light-shielding agents selected from yellow ferric oxide, ferric oxide, titanium dioxide, and zinc oxide.

12. A method for producing a mirabegron sustained-release formulation, comprising: a) granulating mirabegron, polyethylene oxide with an average molecular weight of 1 to 8 million, and one or more water-conducting components selected from gum arabic powder, isomalt hydrate, polyvinyl alcohol / polyethylene glycol graft copolymer, pullulan, trehalose, erythritol, xanthan gum, hydroxypropyl cellulose, DL-malic acid, sodium hydrogen phosphate hydrate, and sodium dihydrogen phosphate hydrate to obtain granules; b) mixing the granules, an antioxidant, and a lubricant to obtain a tablet powder; c) compressing the tablet powder to obtain a plain tablet; and d) film coating the plain tablet to obtain a film-coated tablet.

13. The method according to claim 12, wherein the granulation in step a) is carried out with the addition of a sustained-release regulator.

14. The method according to claim 12 or 13, wherein the granulation in step a) is granulation using water.

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