Sustained-release preparation

Abstract

To provide a sustained-release mirabegron preparation that exhibits favorable sustained-release properties and allows control of release profile depending on a desired purpose.SOLUTION: A sustained-release preparation comprises mirabegron, a polyethylene oxide having an average molecular weight of 1,000,000 to 8,000,000, and at least one water-retentive component selected from the group consisting of arabic gum powder, isomal hydrate, polyvinyl alcohol-polyethylene glycol graft copolymer, pullulan, trehalose, erythritol, xanthan gum, hydroxypropyl cellulose, DL-malic acid, disodium hydrogen phosphate hydrate, and sodium dihydrogen phosphate hydrate.SELECTED DRAWING: None

Description

[Technical Field]

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

[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 commercially available as selective β3-adrenergic receptor agonists for the treatment of overactive bladder under the name "Betanis (registered trademark) Tablets" (hereinafter referred to as "approved preparations").

[0003] Overactive bladder (OAB) is a lower urinary tract symptom (urinary dysfunction) characterized by urinary urgency and frequency due to sudden, involuntary bladder contractions. It can also be accompanied by nocturia and urge incontinence. OAB can be broadly divided into two etiologies: neurogenic and non-neurogenic. Urinary frequency is defined as "urinating 7-8 times or more during the day and 2 times or more during the night," while urinary incontinence is defined as "a condition in which involuntary or unconscious leakage of urine becomes a social and hygienic problem." OAB significantly reduces quality of life due to urinary frequency and incontinence, placing a burden not only on the patient but also on their family and caregivers. In Japan, an estimated 12.4% (8.1 million people) of the population aged 40 or older suffer from OAB.

[0004] Because overactive bladder is thought to be caused by a latent detrusor overactivity, muscarinic receptor antagonists, which have the effect of inhibiting bladder contraction, have been widely used to treat overactive bladder. However, because these drugs are accompanied by side effects such as difficulty in urination, increased residual urine volume, and urinary retention, mirabegron, a selective β3 adrenergic receptor agonist, has been developed to reduce these side effects. In addition, because overactive bladder treatment requires continuous action and limiting side effects, sustained-release preparations have been developed to maintain a constant blood concentration of mirabegron.

[0005] Proposed sustained-release formulations of mirabegron include those that contain a hydrogel-forming polymer such as polyethylene oxide and a hydrophilic additive such as polyethylene glycol for allowing water to penetrate the formulation. The hydrophilic additive guides water into the hydrogel, allowing the formulation to move through the gastrointestinal tract and gradually release the drug without excessive release (Patent Document 1, Non-Patent Document 1). Furthermore, a controlled-release pharmaceutical composition containing a hydrogel-forming polymer such as polyethylene oxide and a hydrophilic base such as erythritol has been disclosed for the purpose of improving stability (Patent Document 2). Furthermore, sustained-release tablets containing polyethylene oxide and hydrophilic additives such as hypromellose and hydroxypropyl cellulose for the purpose of suppressing discoloration and swelling have 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 Summary of the Invention [Problem to be solved by the invention]

[0008] An object of the present invention is to provide a stable sustained-release preparation of mirabegron that exhibits good sustained-release properties, the sustained-release properties of which can be controlled according to the purpose, and a method for producing the sustained-release preparation. [Means for solving the problem]

[0009] As a result of investigations aimed at solving the above-mentioned problems, the present inventors have discovered a method for producing a sustained-release formulation containing a specific polyethylene oxide and a water-conductive component, which has the same dissolution behavior as an approved formulation, i.e., is bioequivalent to the approved formulation, has excellent stability of mirabegron, and can be easily produced using ordinary formulation manufacturing equipment. That is, the present invention relates to the following 1) and 2). 1) A sustained-release formulation containing mirabegron, polyethylene oxide having an average molecular weight of 1 to 8 million, and one or more water-conducting ingredients selected from powdered acacia, isomaltulose 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 sustained-release formulation of mirabegron, comprising: a) a step of granulating mirabegron, polyethylene oxide having an average molecular weight of 1,000,000 to 8,000,000, and one or more water-conductive ingredients selected from powdered acacia, isomaltulose 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 a granulated product; b) a step of mixing the granulated product, an antioxidant, and a lubricant to obtain a tableting powder; c) a step of compressing the tableting powder to obtain uncoated tablets; and d) a step of film-coating the uncoated tablets to obtain film-coated tablets. [Effects of the Invention]

[0010] The sustained-release formulation of the present invention contains mirabegron, specific polyethylene oxide, and a water-conductive component, and exhibits good sustained-release properties that can be controlled according to the purpose. It also has excellent stability of mirabegron and can be easily manufactured using ordinary formulation equipment through processes such as granulation, mixing, and tableting. DETAILED DESCRIPTION OF THE INVENTION

[0011] The sustained-release formulation of the present invention is a sustained-release formulation that exhibits good sustained-release properties and whose sustained-release properties can be controlled according to the purpose, and can be, for example, a formulation that has dissolution behavior similar to that of an already approved formulation and is bioequivalent. Specifically, the mirabegron sustained-release formulation of the present invention exhibits a dissolution rate of 10 to 30% by mass in 60 minutes and 20 to 50% by mass in 120 minutes under conditions of a single liquid paddle at 50 rpm. Under conditions of a water paddle at 50 rpm, the dissolution rate is 15 to 55% by mass in 300 minutes, 35 to 65% by mass in 420 minutes, and 70 to 95% by mass in 720 minutes. Under conditions of a pH 7.5 paddle at 200 rpm, the dissolution rate is 15 to 55% by mass in 120 minutes, 35 to 65% by mass in 180 minutes, and 70 to 95% by mass in 300 minutes. Preferred dissolution profiles are 10 to 30% by mass in 60 minutes and 20 to 50% by mass in 120 minutes under conditions of a single liquid paddle at 50 rpm. Under conditions of water paddle 50 rpm, the dissolution rate is 18 to 52 mass% in 300 minutes, 30 to 62 mass% in 420 minutes, and 65 to 100 mass% in 720 minutes. Under conditions of pH 7.5 paddle 200 rpm, the dissolution rate is 18 to 60 mass% in 120 minutes, 38 to 62 mass% in 180 minutes, and 75 to 100 mass% in 240 minutes.

[0012] The sustained-release formulation of the present invention contains mirabegron, a specific polyethylene oxide, and a water-conductive component. Furthermore, the mirabegron sustained-release formulation of the present invention is in a state in which mirabegron, polyethylene oxide, and the water-conductive component are uniformly dispersed and mixed. Unless otherwise specified in the present invention, the use of each pharmaceutical excipient is in accordance with the use of pharmaceutical excipients in the Pharmaceutical Excipients Dictionary.

[0013] The mirabegron of the present invention can be mirabegron or a pharmaceutically acceptable salt thereof. 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 allows for easy dissolution and easy pharmaceutical preparation. 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 analyzer. An example of a laser diffraction / scattering particle size analyzer is the DMS2 Ver. 11.1.0-257F2 manufactured by Microtrack Bell Corporation.

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

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

[0017] Polyethylene oxide is a base component that forms a hydrogel in the presence of water and is a linear polymer formed by polymerization of ethylene glycol. The polyethylene oxide used in the present invention has a molecular weight that allows it to form a hydrogel, but does not dissolve quickly in the digestive tract, and is almost completely dissolved in the end. The average molecular weight of the polyethylene oxide is 1,000,000 to 8,000,000, preferably 1,000,000 to 4,000,000, more preferably 1,500,000 to 3,000,000, and even more preferably 2,000,000±500,000. In the present invention, average molecular weight refers to the average molecular weight expressed as number average molecular weight unless otherwise specified. The viscosity of the polyethylene oxide is, for example, 12 mPa·s or more in a 5% aqueous solution at 25°C, preferably 12 mPa·s or more in a 5% aqueous solution at 25°C and 40,000 mPa·s or less in a 1% aqueous solution at 25°C, more preferably 400 mPa·s or more in a 2% aqueous solution at 25°C and 7,500 mPa·s or less in a 1% aqueous solution at 25°C, even more preferably 400 mPa·s or more in a 2% aqueous solution at 25°C and 5,500 mPa·s or less in a 1% aqueous solution at 25°C, and most preferably 2,000-4,000 mPa·s in a 2% aqueous solution at 25°C.

[0018] Examples of such polyethylene oxide include polyethylene oxide 7000K, polyethylene oxide 5000K, trade name Polyox WSR-308 [number average molecular weight: 8 million, viscosity: 10,000-15,000 mPa·s (1% aqueous solution at 25°C)], Polyox WSR-303 [number average molecular weight: 7 million, viscosity: 7,500-10,000 mPa·s (1% aqueous solution at 25°C)], Polyox WSR Coagulant [number average molecular weight: 5 million, viscosity: 5,500-7,500 mPa·s (1% aqueous solution at 25°C)], Polyox WSR-301 [number average molecular weight: 4 million, viscosity: 1,650-5,500 mPa·s (1% aqueous solution at 25°C)], and Polyox Examples include WSR-N-60K [number average molecular weight: 2 million, viscosity: 2000-4000 mPa·s (2% aqueous solution at 25°C)] and Polyox WSR-N-12K [number average molecular weight: 1 million, viscosity: 400-800 mPa·s (2% aqueous solution at 25°C)].

[0019] The particle size of the polyethylene oxide of the present invention does not particularly affect the sustained release properties, but in view of ease of production of sustained-release preparations and ease of granulation, an average particle size of 75 to 840 μm is preferred, and an average particle size of 75 to 149 μm is more preferred.

[0020] The content of polyethylene oxide in the sustained-release preparation 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 even more preferably 20 to 35% by mass, based on the mass of the preparation. When the content of polyethylene oxide is within the above range, excellent sustained-release properties are exhibited.

[0021] To adjust the sustained release of the sustained-release preparation of the present invention, the preparation may contain sustained-release regulators such as polyethylene oxide having an average molecular weight of 900,000 or less, which is different from the polyethylene oxide having an average molecular weight of 1 to 8,000,000, hydrogel-forming polymers other than polyethylene oxide, sodium chloride, sodium acetate, magnesium aluminometasilicate hypromellose, etc. Here, adjusting the sustained release means increasing or decreasing the slope of the linear dissolution rate (dissolution rate) in a dissolution test using various dissolution media, which dissolves almost linearly from time 0 to the time when the dissolution rate reaches 85%.

[0022] Examples of polyethylene oxides having an average molecular weight of 900,000 or less include polyethylene oxides having an average molecular weight of preferably 600,000 or less, more preferably 400,000 or less, even more preferably 200,000 or less, and preferably 20,000 or more, more preferably 80,000 or more, and even more preferably 100,000 or more. Polyethylene oxides having these average molecular weights can be used alone or in combination of two or more. When using one type of 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 oxide of such a molecular weight. Examples of polyethylene oxides with an average molecular weight of 900,000 or less include polyethylene oxide 200K, and commercially available products include Polyox WSR-1105 [number average molecular weight: 900,000, viscosity: 8,800-17,600 mPa·s (5% aqueous solution at 25°C)], Polyox WSR-205 [number average molecular weight: 600,000, viscosity: 4,500-8,800 mPa·s (5% aqueous solution at 25°C)], Polyox WSR N-3000 [number average molecular weight: 400,000, viscosity: 2,250-4,500 mPa·s (5% aqueous solution at 25°C)], Polyox WSR-N-750 [number average molecular weight: 300,000, viscosity: 600-1,200 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 at 25°C)], and Polyox Examples include WSR-N-10 [number average molecular weight: 100,000, viscosity: 12-50 mPa·s (5% aqueous solution at 25°C)] (manufactured by DOW).

[0023] Therefore, in the sustained-release preparation of the present invention, a preferred embodiment is one in which polyethylene oxide having an average molecular weight of 2,000,000 and a viscosity of 2,000-4,000 mPa·s (2% aqueous solution at 25°C) is used in combination with polyethylene oxide having an average molecular weight of 600,000 or less, such as polyethylene oxide having an average molecular weight of 600,000 and a viscosity of 4,500-8,800 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 polymeric substances include hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, carboxyvinyl polymers, and macrogol, such as macrogol 20000 or macrogol 35000.

[0025] The amount (mass) of the sustained-release regulator to be added relative to the polyethylene oxide having an average molecular weight of 1,000,000 to 8,000,000 is 100:5 to 100:35, preferably 100:10 to 100:30.

[0026] The water-conducting component of the present invention is a component that conducts water into a composition in which polyethylene oxide having an average molecular weight of 1,000,000 to 8,000,000 and mirabegron are uniformly mixed, and that, upon contact with water, forms a hydrogel not only outside but also inside the composition. Examples of water-conducting components include polymer gels that partially dissolve and swell in water to form a water-soluble gel that conducts water inside, insoluble porous substances that conduct water through their pores, and soluble substances that dissolve in water to form pores in the composition that conduct water.

[0027] Examples of such water-conductive components include gum arabic powder, isomaltulose hydrate, polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat (registered trademark) IR), pullulan, gum arabic powder, isomaltulose 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, gum arabic, 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 sodium monohydrogen phosphate, meta Sodium phosphate, sodium lauryl sulfate, sodium benzoate, maltitol, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, aspartame, hypromellose, hydroxyethylcellulose, carmellose sodium, polyvinyl alcohol, copolypidene, carmellose, anhydrous calcium hydrogen phosphate, magnesium aluminometasilicate, magnesium aluminosilicate, calcium silicate, porous silicon dioxide, erythritol, sodium stearyl fumarate, L-glutamic acid, L-arginine, tomato Examples of suitable surfactants include sorbitan starch, dextrin, ascorbic acid, sodium ascorbate, sodium chloride, potassium chloride, as well as carboxyvinyl polymers, chitosans, mannans, galactomannans, xanthans, mannans, galactomannans, xanthans, carrageenans, acrylates, aminoalkyl methacrylate copolymers, methacrylic acid copolymers, polyacid anhydrides, polyamino acids, poly(methyl vinyl ether / maleic anhydride) polymers, glucans, etc. In the present invention, gum arabic powder, isomaltulose hydrate,The additive is at least one 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, and is preferably at least one selected from powdered gum arabic, isomaltulose hydrate, polyvinyl alcohol-polyethylene glycol graft copolymer, and pullulan.

[0028] The content of the water-conductive component is not particularly limited as long as it is a proportion that can control the release of mirabegron to an extent that is not affected by food, and is, for example, 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 of the formulation.

[0029] The sustained-release preparation of the present invention is a composition in which mirabegron, polyethylene oxide having an average molecular weight of 1,000,000 to 8,000,000, and a water-conductive component are uniformly mixed. It can be produced by mixing and / or granulating mirabegron, polyethylene oxide having an average molecular weight of 1,000,000 to 8,000,000, and the water-conductive component, and then molding the mixture. Granulation is preferred from the viewpoints of content uniformity and tabletability. Here, the mixing, granulation, and molding can be carried out according to conventional methods in the pharmaceutical technology field. Furthermore, during the above-mentioned mixing, granulation, and / or molding, other pharmacologically acceptable pharmaceutical additives described below can be used as desired.

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

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

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

[0033] Lubricants include, for example, magnesium stearate, calcium stearate, talc, colloidal silica, and the like.

[0034] Examples of disintegrants include lactose, sucrose, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethylstarch 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 hydroxypropyl cellulose, sodium carboxymethylcellulose, gum arabic, dextrin, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminometasilicate.

[0036] The antioxidant may be one that does not affect the dissolution behavior, and examples thereof include dibutylhydroxytoluene, propyl gallate, butylhydroxyanisole, ascorbic acid, sodium ascorbate, erythorbic acid, sodium nitrite, sodium bisulfite, sodium pyrosulfite, citric acid, and sodium edetate, with dibutylhydroxytoluene, propyl gallate, and sodium ascorbate being preferred, and dibutylhydroxytoluene being more preferred. These antioxidants are expected to inhibit the formation of polyethylene oxide and other products of the components of the sustained-release formulation of the present invention due to oxidation components such as oxygen.

[0037] Examples of coloring agents 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, ferric oxide (red), titanium oxide, yellow ferric oxide, caramel, talc, etc. These coloring agents are expected to suppress the decomposition of mirabegron by light.

[0038] Examples of light-blocking agents include titanium oxide, calcium carbonate, zinc oxide, talc, iron oxides such as yellow ferric oxide, ferric oxide, and black ferric oxide, Food Yellow No. 5, and Food Red No. 102, with titanium oxide and calcium carbonate being preferred. These light-blocking 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 singly or in combination of two or more. These may be used in appropriate amounts, for example, antioxidants may be used in an amount of 0.025% to 0.25% by mass in the formulation. Furthermore, stabilizers may be used in an amount of 0.05% to 1% by mass in the formulation. Among pharmaceutical additives, macrogol, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hypromellose, lactose, mannitol, etc. are expected to suppress mirabegron analogues in the formulation.

[0041] The obtained uncoated tablets may be film-coated using a film-coating agent and its additives that are generally used in the pharmaceutical field. Here, the film coating agent is not particularly limited, but examples thereof include cellulose-based film coating agents such as carmellose, carmellose sodium, carmellose calcium, hydroxypropyl cellulose, hypromellose, hydroxyethyl cellulose, hydroxymethyl cellulose, methyl cellulose, and carboxymethyl cellulose, as well as gum arabic powder, gelatin pullulan, dextrin, sodium carboxymethyl starch, sodium alginate, polyvinylpyrrolidone, and polyvinyl alcohol, of which cellulose-based film coating agents are preferred, and hypromellose is more preferred.

[0042] The plasticizer is not particularly limited, but examples thereof 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., and preferably polyethylene glycol or triacetin.

[0043] The lubricant for film coating is not particularly limited, but examples thereof include talc, hydrous 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, and preferably talc.

[0044] Examples of the pigment for film coating include those described above as colorants and / or light-blocking agents, and preferred examples include yellow ferric oxide, ferric oxide, and titanium oxide.

[0045] Examples of solvents for dissolving / suspending the film coating agent include alcohols such as methanol, ethanol, and isopropyl alcohol, acetone, toluene, hexane, methyl ethyl ketone, and water, or mixed solvents thereof, with ethanol and water being preferred, and water being more preferred.

[0046] In the film-coated tablets, there is no clear limitation on the amount of coating of the film coating portion. For example, for uncoated tablets with a mass of 250 mg, it is preferable that the coating amount be in the range of 2 to 20 mg / tablet, and more preferably in the range of 4 to 12 mg / tablet, and for uncoated tablets with a mass of 125 mg, it is preferable that the coating amount be in the range of 1 to 10 mg / tablet, and more preferably in the range of 2 to 8 mg / tablet.

[0047] The sustained-release tablet of the present invention mainly contains a hydrophilic component (polyethylene oxide) having an average molecular weight of 1,000,000 to 8,000,000 and a water-conductive component, and therefore the moisture content is preferably 0.01 to 10% by mass, more preferably 0.1 to 7% by mass, and even more preferably 0.5 to 5% by mass, based on the total weight of the tablet. The moisture content can be measured using an infrared moisture meter (FD-660, Kett Electric Laboratory) at 110°C for 15 minutes.

[0048] As mentioned above, in order to suppress moisture absorption of the sustained-release tablets of the present invention, polychlorotrifluoroethylene copolymer, cycloolefin copolymer, polychlorotetrafluoroethylene, vinylidene chloride, etc. can be used as the primary packaging material, and it is further preferable that the temporary packaging is packaged in aluminum film / polyethylene pillow packaging.

[0049] The methods for producing the sustained-release preparation of the present invention are explained below, but the present invention is not limited thereto. The sustained-release preparation of the present invention can be produced by a conventional method in the field of pharmaceutical manufacturing, including one or more steps selected from, for example, pulverization, granulation, mixing, sizing, tableting, film coating, etc. For example, it can be produced by the following steps a) to d). a) a step of granulating mirabegron, polyethylene oxide having an average molecular weight of 1,000,000 to 8,000,000, and one or more water-conductive ingredients selected from powdered acacia, isomaltulose 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 a granulated product; b) mixing the granules, an antioxidant, and a lubricant to obtain a tablet powder; c) compressing the tablet powder to obtain plain tablets; d) A step of film-coating the plain tablets to obtain film-coated tablets.

[0050] In order to obtain the desired particle size, mirabegron, polyethylene oxide having an average molecular weight of 1,000,000 to 8,000,000, and the water-conductive component can be crushed or pulverized. A conventional crushing or pulverizing method can be used for crushing or pulverizing. Examples of the crushing or pulverizing method include an impact pulverizer, a wet-dry granulator, a crushing granulator, and an airflow pulverizer.

[0051] Conventional granulation methods can be used for granulation. Examples include fluidized bed granulation, agitation granulation, tumbling fluidized bed granulation, extrusion granulation, melt granulation, and dry granulation. Granulation equipment includes, for example, a fluidized bed granulator, a granulation coating device equipped with a horizontal rotating disk with a smooth powder contact area, a granulation coating device equipped with a ventilated area and a smooth-surfaced rotating disk installed below the fluidized bed, and a dry granulation device that compresses, molds, crushes, and sizes the raw material powder. Wet granulation, which has a high solvent removal rate, is preferred because it has little effect on dissolution and drying of the solvent, such as water, and fluidized bed granulation is also suitable because it allows immediate drying.

[0052] When dry granulation is used, for example, mirabegron, polyethylene oxide, a water-conductive component, and additives such as a lubricant are compressed and molded in a dry granulator, and then coarsely crushed and sized to obtain granules of the desired size.

[0053] When wet granulation is used, for example, mirabegron, polyethylene oxide with an average molecular weight of 1,000,000 to 8,000,000, a water-conductive component, and additives such as excipients are fluidized together in a fluidized bed granulation method, and a required amount of water or a liquid containing a water-conductive component and / or a binder is sprayed onto the mixture. The liquid containing the water-conductive component is prepared by dissolving or dispersing the essential components in a solvent such as water, ethanol, or methanol. Among the solvents, ethanol and methanol dissolve mirabegron to a certain extent, but are likely to affect the properties of the active pharmaceutical ingredient, such as solubility and stability, so water is preferred. These solvents can also be mixed and used as appropriate. In the agitation granulation method, mirabegron, polyethylene oxide with an average molecular weight of 1,000,000 to 8,000,000, a water-conductive component, and other pharmaceutical additives are agitated while a liquid containing a binder is added to the mixture, followed by granulation and drying.

[0054] The amount of water used during granulation is not particularly limited, as long as it is an amount that can uniformly dissolve or suspend (disperse) the binder and / or other pharmaceutical additives. When the water-conductive component is used in a solid state, there is no particular limitation on the amount, as long as it is an amount that can granulate polyethylene oxide having an average molecular weight of 1,000,000 to 8,000,000. The amount added is usually 100 to 300% by mass of the polyethylene oxide. The rate of water addition during granulation is not particularly limited, as long as it is a rate that does not result in a non-uniform granulation consisting of powdery agglomerates and untreated powder.

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

[0056] Drying can be carried out after wet granulation. The subsequent drying step can be carried out using a drying method typically used in the field of pharmaceutical manufacturing, such as a fluidized bed granulator, a tray dryer, or a vacuum dryer, as long as the granulated material is dried. After granulation, it is preferable to adjust the particle size of the granulated material by sieving, crushing, sieving, etc. The particle size of the granulated material is 1 mm or less, preferably 0.8 mm or less, based on the mesh size that passes through. For sieving, crushing, and sieving, equipment normally used in pharmaceutical manufacturing processes, such as a Comil, can be used.

[0057] Other pharmaceutical additives can be added or mixed as needed during or after granulation. Ingredients added during granulation include binders, excipients, disintegrants, etc. When adding other pharmaceutical additives after granulation and mixing them (also called "post-addition"), excipients, disintegrants, antioxidants, lubricants, etc. can be mixed.

[0058] Examples of tableting methods include direct tableting, in which mirabegron, a water-conductive component, polyethylene oxide having an average molecular weight of 1,000,000 to 8,000,000, and suitable additives are mixed together and then compressed to form tablets; wet granulation, in which mirabegron, a water-conductive component, polyethylene oxide having an average molecular weight of 1,000,000 to 8,000,000, and additives are mixed together and then a binder liquid is sprayed onto the mixture to form granules; and melt granulation, in which mirabegron, a water-conductive component, polyethylene oxide having an average molecular weight of 1,000,000 to 8,000,000, and a suitable low-melting-point substance are mixed together and then heated to form granules, followed by tableting. Examples of tableting machines include rotary tableting machines and single punch tableting machines, but there are no particular limitations on the machine as long as it is a method for producing compressed products (preferably tablets) in a typical pharmaceutical manner.

[0059] After tableting, a pan coating machine may be used to coat the tablets with a film, for example, at 1% by mass to 5% by mass per tablet. Film coating can be carried out according to a standard method for manufacturing pharmaceuticals. [Example]

[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 hereinafter unless otherwise specified), 127.1 parts by mass of gum arabic powder (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., gum arabic; the same applies hereinafter), 0.4 parts by mass of dibutylhydroxytoluene, and 2.5 parts by mass of magnesium stearate were mixed in a mortar to prepare a tableting powder, which was compressed using an oval 12.0 x 6.0 punch at a set hardness of 80 N to obtain 250 mg sustained-release tablets containing 50 mg of mirabegron.

[0061] Examples 2 to 4 A 250 mg sustained-release tablet containing 50 mg of mirabegron was obtained in the same manner as in Example 1, except that the water-conductive component, gum arabic powder, was replaced with the components shown in Table 1.

[0062] [Table 1]

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

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

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

[0066] [Table 2]

[0067] [Table 3]

[0068] [Table 4]

[0069] In a dissolution test modeling the human stomach (solution 1 (pH 1.2), paddle 50 rpm), the sustained-release formulations of Examples 1 and 2 suppressed excessive release of mirabegron. In a dissolution test modeling the small intestine (pH 7.5, paddle 200 rpm), the sustained-release formulations of Examples 1 and 2 of the present invention released mirabegron sufficiently. In the dissolution test (water, paddle 50 rpm), which shows the greatest difference in the dissolution behavior of the formulations, the dissolution of the sustained-release formulation of Comparative Example 1 was insufficient. The dissolution behaviors of the sustained-release formulations of Examples 1 and 2 and the control sustained-release formulation of Reference Example 1 were similar, with f2 functions of 42 or more. The sustained-release preparations of Examples 1 and 2 of the present invention exhibit sufficient dissolution properties under various conditions, and are able to achieve dissolution behavior similar to that of the controlled sustained-release preparation of Reference Example 1.

[0070] Example 5 50 parts by weight of mirabegron, 60 parts by weight of polyethylene oxide (molecular weight 2,000,000, Dow Chemical, trade name Polyox WSR N-60K), 10 parts by weight of polyethylene oxide (molecular weight 600,000, Dow Chemical, trade name WSR 205), and 119.6 parts by weight of gum arabic (Sanei Pharmaceutical Trading, Arabic Coal JPF) were charged into a fluidized bed granulator and granulated with purified water containing 7.5 parts by weight of hydroxypropyl cellulose to obtain sustained-release granules. 247.1 parts by weight of the sustained-release granules were mixed with 0.4 parts by weight of dibutylhydroxytoluene and 2.5 parts by weight of magnesium stearate, and then compressed in a rotary tablet press using an oval 12.0 x 6.0 punch at 30 rpm and a set hardness of 120 N to obtain 250 mg uncoated tablets. A coating liquid 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 tablets in a coating device to obtain film-coated sustained-release preparations (tablets) containing 50 mg of mirabegron and weighing 257.5 mg per tablet.

[0071] Example 6 25 parts by weight of mirabegron, 60 parts by weight of polyethylene oxide (molecular weight 2,000,000, Dow Chemical, trade name Polyox WSR N-60K), 10 parts by weight of polyethylene oxide (molecular weight 100,000, Dow Chemical, trade name N10), and 144.6 parts by weight of gum arabic powder were charged into a fluidized bed granulator and granulated with purified water containing 7.5 parts by weight of hydroxypropyl cellulose to obtain sustained-release granules. 247.1 parts by weight of the sustained-release granules were mixed with 0.4 parts by weight of dibutylhydroxytoluene and 2.5 parts by weight of magnesium stearate, and then compressed in a rotary tablet press using an oval 12.0 x 6.0 punch at a rotation speed of 30 rpm and a set hardness of 120 N to obtain 250 mg uncoated tablets. A coating liquid 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 tablets in a coating device to obtain film-coated sustained-release preparations (tablets) containing 50 mg of mirabegron and weighing 257.5 mg per tablet.

[0072] Example 7 50 parts by weight of mirabegron, 60 parts by weight of polyethylene oxide (molecular weight 2,000,000, Dow Chemical, trade name Polyox WSR N-60K), 10 parts by weight of polyethylene oxide (molecular weight 100,000, Dow Chemical, trade name N10), and 119.6 parts by weight of isomaltulose hydrate (BENEO, Galen IQ801) were charged into a fluidized bed granulator and granulated with purified water containing 7.5 parts by weight of hydroxypropyl cellulose to obtain sustained-release granules. 247.1 parts by weight of the sustained-release granules were mixed with 0.4 parts by weight of dibutylhydroxytoluene and 2.5 parts by weight of magnesium stearate, and then compressed in a rotary tablet press using an oval 12.0 x 6.0 punch at a rotation speed of 30 rpm and a set hardness of 120 N to obtain 250 mg uncoated tablets. 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 tablets in a coating device to obtain film-coated sustained-release preparations (tablets) containing 50 mg of mirabegron and weighing 257.5 mg per tablet. The moisture content of the tablets was 1.9%.

[0073] Example 8 25 parts by weight of mirabegron, 60 parts by weight of polyethylene oxide (molecular weight 2,000,000, Dow Chemical, trade name Polyox WSR N-60K), 10 parts by weight of polyethylene oxide (molecular weight 100,000, Dow Chemical, trade name N10), and 144.6 parts by weight of isomaltulose hydrate were charged into a fluidized bed granulator and granulated with purified water containing 7.5 parts by weight of hydroxypropyl cellulose to obtain sustained-release granules. 247.1 parts by weight of the sustained-release granules were mixed with 0.4 parts by weight of dibutylhydroxytoluene and 2.5 parts by weight of magnesium stearate, and then compressed in a rotary tablet press using an oval 12.0 x 6.0 punch at a rotation speed of 30 rpm and a set hardness of 120 N to obtain 250 mg uncoated tablets. A coating liquid 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 tablets in a coating device to obtain film-coated sustained-release preparations (tablets) containing 50 mg of mirabegron and weighing 257.5 mg per tablet.

[0074] (Dissolution test) In Examples 5 to 7, Reference Example 1, and Comparative Example 1, dissolution behavior was measured under three conditions based on the dissolution test of the Japanese Pharmacopoeia: (1) Solution 1, paddle 50 rpm, (2) water, paddle 50 rpm, and (3) pH 7.5, paddle 200 rpm. Comparative Example 1 did not show a dissolution behavior similar to that of Reference Example 1 under the condition of (2) water, paddle 50 rpm, so the dissolution test under the condition of (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 preparations of Examples 5 to 7 of the present invention have the same dissolution properties as the approved preparation of Reference Example 1 in each dissolution medium that reflects the conditions in the body, and have excellent sustained-release properties.

[0080] (Stability test) The product was 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] Related substance measurement methods: Add a water / acetonitrile mixture (1:1) to one tablet containing 50 mg of mirabegron or one tablet containing 25 mg of mirabegron and stir to make exactly 50 mL and 25 mL, respectively. Filter this solution through a membrane filter with a pore size of 0.45 μm or less. Discard the first 2 mL of filtrate, and use the next filtrate as the sample solution. Accurately measure 1 mL of this solution and add a water / acetonitrile mixture (1:1) to make exactly 100 mL, which will be used as the standard solution. Take exactly 10 μL of each of the sample solution and standard solution and test by liquid chromatography under the following conditions. Measure the peak area of each solution using the automatic 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 : Total area of each peak other than mirabegron obtained from the sample solution A S : Peak area of mirabegron obtained from standard solution Test conditions Detector: ultraviolet absorption photometer (measurement wavelength: 250 nm) Column: YMC-Triart C18 (inner diameter 4.6 mm x length 150 mm, 3.5 μm) Column temperature: constant temperature around 40°C Sample temperature: 5℃ Mobile phase A: 4.783 g of sodium dihydrogen phosphate dihydrate and 2.773 g of disodium hydrogen phosphate, mixed with water to make exactly 1000 mL, and mixed 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 affinity of 0.5% or less and are more stable than the approved formulation of Reference Example 1.

[0085] (Formulation Example 1) 50 parts by weight of mirabegron, 70 parts by weight of polyethylene oxide (molecular weight 2 million, Dow Chemical, trade name Polyox WSR N-60K), and 119.6 parts by weight of powdered gum arabic (Sanei Pharmaceutical Trading, Arabic Coal JPF) were placed in a fluidized bed granulator and granulated with purified water containing 7.5 parts by weight of hydroxypropyl cellulose to obtain sustained-release granules. 247.1 parts by weight of the sustained-release granules were mixed with 0.4 parts by weight of dibutylhydroxytoluene and 2.5 parts by weight of magnesium stearate, and then compressed in a rotary tablet press using an oval 12.0 x 6.0 punch at 30 rpm and a set hardness of 80 N to obtain 250 mg uncoated tablets. A coating liquid 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 tablets in a coating device to obtain film-coated sustained-release preparations (tablets) containing 50 mg of mirabegron and weighing 257.5 mg per tablet.

[0086] (Formulation Examples 2 to 11) A sustained-release preparation (plain tablet) of 250 mg containing 50 mg of miraberon was obtained by the same method as in Example 5, except that gum arabic was replaced with the water-conductive component shown in Table 5.

[0087] [Table 11]

[0088] (Formulation Example 12) 25 parts by weight of mirabegron, 55 parts by weight of polyethylene oxide (molecular weight 2 million, Dow Chemical, trade name Polyox WSR N-60K), 15 parts by weight of polyethylene oxide 200K, and 144.6 parts by weight of isomaltulose hydrate were charged into a fluidized bed granulator and granulated with purified water containing 7.5 parts by weight of hydroxypropyl cellulose. The granules were sieved through a 0.8 mm sieve to obtain sustained-release granules with a particle size of 0.8 mm or less. 247.1 parts by weight of the sustained-release granules were mixed with 0.4 parts by weight of dibutylhydroxytoluene and 2.5 parts by weight of magnesium stearate, and then compressed in a rotary tablet press using an oval 12.0 x 6.0 punch at a rotation speed of 30 rpm and a set hardness of 120 N to obtain 250 mg uncoated tablets. A coating liquid 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 tablets in a coating device to obtain film-coated sustained-release preparations (tablets) containing 50 mg of mirabegron and weighing 257.5 mg per tablet.

[0089] The mirabegron sustained-release tablet of the present invention satisfies the following requirements as a pharmaceutical preparation. (1) There are no tableting problems such as capping or sticking during tableting, and the content of the active ingredient is uniform. (2) It must be strong enough to avoid chipping or cracking during manufacturing or transportation. (3) There is no significant decrease in the dissolution properties of mirabegron sustained-release tablets over time, and the dissolution properties remain similar or equivalent to those at the initial stage. (4) The tablet weight is less than 650 mg, making it relatively easy to swallow.

Claims

1. A sustained-release preparation comprising mirabegron, polyethylene oxide having an average molecular weight of 1,000,000 to 8,000,000, and one or more water-conductive components selected from acacia powder, isomaltulose 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. 2. The sustained-release preparation according to claim 1, wherein the water-conductive component is one or more selected from the group consisting of gum arabic powder, isomaltulose hydrate, polyvinyl alcohol-polyethylene glycol graft copolymer, and pullulan.

3. 2. The sustained-release preparation according to claim 1, wherein the content of the water-conductive component in the preparation is 5 to 80% by mass.

4. 2. The sustained-release preparation according to claim 1, wherein the content of the water-conductive component in the preparation is 40 to 65% by mass.

5. 2. The sustained-release preparation according to claim 1, wherein the content of polyethylene oxide having an average molecular weight of 1,000,000 to 8,000,000 in the preparation is 10 to 80% by mass.

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

7. 2. The sustained-release formulation of claim 1, further comprising one or more sustained-release regulators selected from polyethylene oxide having an average molecular weight of 900,000 or less, sodium chloride, sodium acetate, and magnesium aluminometasilicate hypromellose.

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

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

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

11. 2. The sustained-release formulation of claim 1, comprising one or more sunscreens selected from yellow ferric oxide, ferric oxide, titanium oxide, and zinc oxide.

12. A method for producing a sustained-release formulation of mirabegron, comprising: a) a step of granulating mirabegron, polyethylene oxide having an average molecular weight of 1,000,000 to 8,000,000, and one or more water-conductive components selected from powdered arabic, isomaltulose 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 a granulated product; b) a step of mixing the granulated product, an antioxidant, and a lubricant to obtain a powder for tableting; c) a step of compressing the powder for tableting to obtain uncoated tablets; and d) a step of film-coating the uncoated tablets to obtain film-coated tablets.

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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