JP2022090391A - Release-controlled tablet containing mirabegron and method for producing the same - Google Patents

Abstract

To provide a novel mirabegron release-controlled preparation having controlled releasability.SOLUTION: A release-controlled tablet contains at least one of an acidic pH modifier and a water-insoluble disintegrator, alginate, and mirabegron or a pharmaceutically acceptable salt thereof or a solvate thereof.SELECTED DRAWING: Figure 2

Description

The present invention relates to a release controlled tablet containing mirabegron or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient, and a method for producing the same. The present invention relates to a method of controlling the release of mirabegron from a tablet.

Mirabegron is a compound represented by the following formula (I), and its chemical name is 2- (2-amino-1,3-thiazole-4-yl) -N- [4- (2-{[(). 2R) -2-hydroxy-2-phenylethyl] amino} ethyl) phenyl] acetamide. Mirabegron can stimulate β3 adrenergic receptors in bladder smooth muscle, enhance urinary storage function by relaxing the bladder, and improve urinary urgency, pollakiuria and urge incontinence in overactive bladder. Mirabegron is currently marketed in the form of tablets.

In order to maintain the efficacy of mirabegron as described above for a long period of time, it is preferable that mirabegron is continuously released from the tablet for a long period of time. Regarding tablets having such properties (referred to as sustained release) (release control tablets), for example, in Patent Document 1, mirabegron is mixed with hypromellose or ethyl cellulose, and the obtained mixed powder is compression-molded to obtain mirabegron. It is described that a release controlled tablet containing the above was produced.

International Publication No. 2011/122523

An object of the present invention is to provide a novel Mirabegron release controlled preparation having sustained release property.

As a result of diligent studies, the present inventors have made mirabegron with improved sustained release by producing tablets using at least one of an acidic pH regulator and a water-insoluble disintegrant, alginate, and mirabegron. The present invention has been completed by finding that it is possible to provide a release-controlled preparation containing. Accordingly, the present invention comprises at least one of an acidic pH regulator and a water-insoluble disintegrant, alginate and, as an active ingredient, Mirabeglon or a pharmaceutically acceptable salt thereof or a solvate thereof. A control tablet is provided.

The present invention comprises a step of obtaining a mixture comprising at least one of an acidic pH adjuster and a water-insoluble disintegrant, alginate, Mirabeglon or a pharmaceutically acceptable salt thereof or a solvate thereof, and a mixture thereof. A release control containing Mirabeglon or a pharmaceutically acceptable salt thereof or a solvate thereof, which comprises a step of granulating the granulated product to obtain a granulated product and a step of compressing the granulated product to obtain a tablet. Provided is a method for producing a tablet.

The present invention is a tablet containing mirabegron or a pharmaceutically acceptable salt thereof or a solvate thereof, which comprises at least one of an acidic pH regulator and a water-insoluble disintegrant and alginate. Provided is a method for controlling the release of mirabegron from.

INDUSTRIAL APPLICABILITY According to the present invention, a release controlled tablet containing mirabegron or a pharmaceutically acceptable salt thereof or a solvate thereof, which has improved sustained release of mirabegron, and a method for producing the same are provided.

It is the result of the dissolution test of the tablet of Example 2, Example 5, Example 7, Example 8 and Comparative Example. It is the result of the dissolution test of the tablet of Example 9. It is the result of the dissolution test of the tablet of Comparative Example, Example 1, Example 2 and Example 3. It is the result of the dissolution test of the tablet of Comparative Example, Example 4, Example 5 and Example 6.

(Release control tablet)
The release-controlled tablet of the present embodiment (hereinafter, also simply referred to as a tablet) contains mirabegron or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient. The pharmaceutically acceptable salt of mirabegron is a salt formed from the compound represented by the above formula (I) and an organic or inorganic acid, which is acceptable for administration to mammals including humans. .. Such pharmaceutically acceptable salts include, for example, hydrochlorides, sulfates, phosphates, acetates, nitrates or carbonates.

The pharmaceutically acceptable solvate of Mirabeglon is a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof, and a solvent that can be administered to mammals including humans. A solid molecule formed from. Examples of such a solvent include water, acetic acid, ethanol and the like.

Hereinafter, the term "mirabegron" includes, unless otherwise specified, the compound represented by the above formula (I), a pharmaceutically acceptable salt thereof, and a solvate thereof. Mirabegron is not particularly limited as long as it is a solid, and may be, for example, a powder.
The particle size of mirabegron is not particularly limited, but for example, the medium diameter (D ₅₀ ) of mirabegron powder is preferably 3 μm or more and 30 μm or less, more preferably 5 μm or more and 25 μm or less, and 8 μm or more and 20 μm or less. It is more preferable to have. In the present specification, this D ₅₀ is based on a volume-based particle size distribution measured using a laser diffraction / scattering type particle size distribution measuring device. Examples of the laser diffraction / scattering type particle size distribution measuring device include "Aerotrack LDSA-SPR" manufactured by Microtrac Bell Co., Ltd. and "Mastersizer 3000" manufactured by Malvern Panalytical Co., Ltd.

In the present embodiment, the content of mirabegron in the tablet is 1% by mass or more and 50% by mass or less of the total mass of the tablet. The lower limit of the content of mirabegron in the tablet is, for example, 1% by mass, 3% by mass, 5% by mass, 10% by mass, 15% by mass, and 20% by mass. The upper limit of the content of mirabegron in the tablet is, for example, 50% by mass, 45% by mass, 40% by mass, 35% by mass, and 30% by mass.

The release controlled tablet of the present embodiment contains at least one of an acidic pH regulator and a water-insoluble disintegrant, and alginate. In this embodiment, the sustained release of mirabegron can be improved by producing tablets using at least one of an acidic pH regulator and a water-insoluble disintegrant. Here, "improvement of sustained release of mirabegron" includes mirabegron in which the release rate of mirabegron from the tablets produced by the present invention into water does not contain an acidic pH regulator and a water-insoluble disintegrant. Refers to being suppressed compared to tablets.
The alginate is not particularly limited, but it is preferable to use a water-soluble alginate. Examples of the water-soluble alginate include sodium alginate, potassium alginate, ammonium alginate, and the like, and sodium alginate is preferably used.
The content of alginate in the tablet is 25% by mass or more and 60% by mass or less of the total mass of the tablet. The lower limit of the content of alginate in tablets is, for example, 25% by mass, 30% by mass, and 35% by mass. The upper limit of the content of alginate in the tablet is, for example, 60% by mass, 58% by mass, 55% by mass, and 52% by mass.
The viscosity of alginate can be 50 mPa · s or more, preferably 200 mPa · s or more, more preferably 400 mPa · s or more, and more preferably 800 mPa · s or more. preferable. Here, the viscosity of alginate in the present specification refers to a value obtained by measuring the viscosity of a 1% by mass solution of alginate based on the rotational viscometer method described in the Japanese Pharmacopoeia.
Examples of the alginate include "Kimika algin I series I-8" (800 to 900 mPa · s) manufactured by Kimika.

An acidic pH regulator is a substance that has the ability to acidify the pH of a solution when dissolved in water. As the acidic pH adjuster, a pharmaceutically acceptable substance is preferable, and it is more preferable to select from organic acids excluding alginic acid and salts thereof or salts thereof. Examples of the organic acid excluding alginic acid and its salt or a salt thereof include citric acid, L-aspartic acid, ascorbic acid or a salt thereof. Of these, citric acid or a salt thereof is preferably contained, and more preferably citric acid or a salt thereof. The acidic pH adjuster may be used alone or in combination of two or more.
The content of the acidic pH regulator in the tablet is 1% by mass or more and 25% by mass or less of the total mass of the tablet. The lower limit of the content of the acidic pH regulator in the tablet is, for example, 1% by mass, 3% by mass, 5% by mass, and 10% by mass. The upper limit of the content of the acidic pH regulator in the tablet is, for example, 25% by mass, 20% by mass, and 15% by mass.

Examples of the water-insoluble disintegrant include carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose or sodium starch glycolate, and it is preferable to select from carboxymethyl cellulose, calcium carboxymethyl cellulose or sodium carboxymethyl cellulose. The water-insoluble disintegrant may be one kind or a combination of two or more kinds.
The content of the water-insoluble disintegrant in the tablet is 1% by mass or more and 25% by mass or less of the total mass of the tablet. The lower limit of the content of the water-insoluble disintegrant in the tablet is, for example, 1% by mass, 3% by mass, 5% by mass, and 10% by mass. The upper limit of the content of the water-insoluble disintegrant in the tablet is, for example, 25% by mass, 20% by mass, and 15% by mass.
It is preferable that both an acidic pH adjuster and a water-insoluble disintegrant are contained.

In this embodiment, pharmaceutically acceptable pharmaceutical additives may be included, if necessary. Such pharmaceutical additives can be appropriately selected from pharmaceutically acceptable stabilizers, lubricants, excipients, binders, sweeteners, colorants, disintegrants other than water-insoluble disintegrants, and the like.

Pharmaceutically acceptable stabilizers include, for example, calcium chloride, calcium chloride hydrate, calcium chloride dihydrate, dibutyl hydroxytoluene, alanine, sodium chloride and the like. The stabilizer may be one kind or a combination of two or more kinds.

Pharmaceutically acceptable lubricants include, for example, talc, magnesium stearate, calcium stearate, stearic acid, light anhydrous silicic acid and the like. The lubricant may be one kind or a combination of two or more kinds.

Pharmaceutically acceptable excipients include, for example, starches, celluloses, sugars, sugar alcohols and the like. Examples of starches include partially pregelatinized starch and corn starch. Examples of celluloses include crystalline cellulose and hydroxypropyl cellulose having a low degree of substitution. Examples of sugars include lactose (also referred to as lactose hydrate) and sucrose. Examples of sugar alcohols include D-sorbitol and D-mannitol. Among them, it is preferable to use D-mannitol. The excipient may be one kind or a combination of two or more kinds.

Pharmaceutically acceptable binders include, for example, polyethylene glycol, hydroxypropyl cellulose, hypromellose, ethyl cellulose, polyvinylpyrrolidone and the like. Among them, it is preferable to use polyethylene glycol or hydroxypropyl cellulose. The binder may be one kind or a combination of two or more kinds.

Pharmaceutically acceptable sweeteners include, for example, acesulfame potassium, sucralose, aspartame, saccharin sodium and the like. The sweetener may be one kind or a combination of two or more kinds.

Examples of the pharmaceutically acceptable colorant include iron sesquioxide and yellow iron sesquioxide. The colorant may be one kind or a combination of two or more kinds.

Examples of the disintegrant other than the water-insoluble disintegrant include adipic acid, sodium hydrogencarbonate, sucrose, dextrin, lactose and the like. The disintegrant other than the water-insoluble disintegrant may be one kind, or two or more kinds may be combined.

The tablets may be further coated if desired. As the coating, a known coating method can be used. For example, a pan coating method, a fluidized bed coating method, or the like can be used. The coating agent can be appropriately selected from pharmaceutically acceptable ones depending on the intended use of the coating. Examples of the coating agent include hypromellose, ethyl cellulose, talc, titanium oxide, silicic acid, hydroxypropyl cellulose, polyvinylpyrrolidone, aminoalkyl methacrylate copolymer, polyvinyl alcohol, polyvinyl alcohol diethylaminoacetate, polyvinyl alcohol acetate phthalate, cellulose acetate phthalate and hypromellose. Examples thereof include phthalate, a copolymer of methacrylic acid, a copolymer of methyl methacrylate and butyl methacrylate, and a copolymer of dimethylaminoethyl methacrylate. The coating agent may be one kind or a combination of two or more kinds.

The tablets may be packaged in PTP packaging, bottle filling, aluminum packaging, or the like, if necessary.
Examples of the material of the PTP packaging include resins such as polyvinyl chloride, polypropylene, polyvinylidene chloride, polychlorotrifluoroethylene, polyethylene, polystyrene or polycarbonate, and metals such as aluminum. These materials may be used alone or in combination of two or more. Examples of the combination include, for example, laminating polyvinyl chloride and polyvinylidene chloride, laminating polyvinyl chloride and polychlorotrifluoroethylene, and the like. It can be packaged by putting a tablet in a pocket molded into a resin sheet formed by molding the above resin by a known method and covering it with aluminum foil.
The PTP package containing the tablets may be further packaged with an aluminum pillow. The aluminum pillow may further contain a desiccant and an oxygen scavenger. Examples of the desiccant include calcium chloride, calcium oxide, magnesium oxide, silica gel, zeolite and the like. Examples of the oxygen scavenger include iron-based oxygen scavengers such as iron powder, organic deoxidizers such as ascorbic acid, isoascorbic acid, hydroquinone and catechol. These desiccants and decarbonizing agents may be used alone, in combination of a plurality of types, or in combination of a desiccant and a deoxidizing agent. Examples of products that combine a desiccant and an oxygen scavenger include "Pharma Keep (registered trademark)" of Mitsubishi Gas Chemical Company, Inc.

(Tablet manufacturing method)
One embodiment of the present invention is a method for producing a controlled release tablet containing mirabegron or a pharmaceutically acceptable salt thereof or a solvate thereof. This manufacturing method will be described below.

First, at least one of an acidic pH regulator and a water-insoluble disintegrant, alginate, mirabegron, and a tablet additive are mixed to obtain a mixture. The mixing can be carried out by a method known in the art. When mixing is carried out by the method, for example, bag mixing may be carried out in which these are placed in an appropriate bag and stirred. When mixing is performed by a machine, a mixer known in the art may be used. The mixer may be either a rotary mixer or a fixed mixer. The rotary mixer is a machine that mixes powder contained in the container by rotating the container itself. The fixed type mixer is a machine that mixes powder contained in the container by rotating a stirring blade, a screw, or the like provided in the container. Examples of the mixer include a V-type mixer, a double conical type mixer, a ribbon type mixer, a conical screw type mixer, and the like. Alternatively, it may be introduced into a device such as a stirring granulator that can also perform the granulation step described later and mixed. The amount of the acidic pH adjuster, the water-insoluble disintegrant, the alginate and the mirabegron and the tablet additive to be mixed can be appropriately set according to the mixer used.

The additive for tablets can be appropriately selected from the above-mentioned compounds. Of the tablet additives, stabilizers, binders, excipients and / or lubricants are preferably used. As the stabilizer, it is preferable to use at least one selected from calcium chloride hydrate, calcium chloride dihydrate and dibutyl hydroxytoluene, and as a binder, polyethylene glycol is preferably used, and as an excipient. It is preferable to use D-mannitol, and magnesium stearate is preferably used as the lubricant.

The acidic pH adjuster, alginate, and tablet additive may be mixed in advance and pulverized by being subjected to an impact crusher or the like. For mixing, the above-mentioned bag or mixer can be used for mixing. The impact type crusher is not particularly limited, and an apparatus known in the art can be used. Examples of such a device include a pin mill and a hammer mill.

Next, the mixture is placed in a granulator and granulated to obtain a granulated product containing mirabegron. The granulator is not particularly limited as long as it does not affect the physical properties of mirabegron. As the granulator, for example, a stirring granulator, a fluidized bed granulator, a dry granulator, or the like can be used. Further, the device may have a drying function. The granulating mixture or granulated product may be classified by subjecting it to a sieve having a specific mesh. By passing through a sieve, the particle size of the granulation mixture or the granulated product can be adjusted to an appropriate size.

Tablets can be obtained by compression-molding the obtained tableting mixture with a tableting machine. A known tableting machine can be used for compression molding. As a known tableting machine, for example, a tabletop tablet molding machine, a rotary type tableting machine, or the like can be used. Alternatively, the mixture obtained by performing the above-mentioned bag mixing can also be obtained by directly subjecting it to a known locking machine for locking.
The resulting tablets may be further coated, if desired. As a coating method, a known coating method can be used. For example, a pan coating method, a fluidized bed coating method, or the like can be used. The coating agent to be used can be appropriately selected from the above.

The mass of the tablet produced is not particularly limited, but a mass in which the tablet can contain at least 50 mg as the compound represented by the formula (I) is preferable. The mass of the tablet is, for example, 50 mg or more and 500 mg or less, preferably 100 mg or more and 400 mg or less, and more preferably 100 mg or more and 300 mg or less per tablet.

The hardness of the produced tablet is not particularly limited, but is preferably 40 N or more and 130 N or less, and more preferably 50 N or more and 120 N or less. Here, the hardness in the present specification refers to a value measured by a method of applying a load to a tablet with an indenter by an electric weight load using a hardness tester.
The tableting pressure at the time of producing a tablet is not particularly limited and may be appropriately set according to the composition and weight of the tablet. The tableting pressure can be set to be, for example, 5 kN or more and 15 kN or less, and is preferably 7 kN or more and 13 kN or less.

One embodiment of the invention is a method of controlling mirabegron release from tablets. Alginic acid by comprising at least one of an acidic pH regulator and a water-insoluble disintegrant and alginate to produce a tablet containing mirabegron or a pharmaceutically acceptable salt thereof or a solvate thereof. It improves the sustained release of Mirabeglon over tablets without acidic pH regulators and / or water-insoluble disintegrants while using the salt as a sustained release base. For example, in a mirabegron elution test in water, the time for the mirabegron concentration to reach the maximum value can be extended. As a result, mirabegron is slowly released from the tablet, and the administration subject to which the tablet is administered can enjoy the pharmacological effect of mirabegron for a long period of time. The details of tablet production in this method are the same as those described for the tablet production method of the present embodiment described above.

Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited thereto.

Various pharmaceutical additives were mixed with mirabegron to produce tablets, and the disintegration time of the tablets and the elution of mirabegron were investigated.
The manufacturing method of each tablet is described below. The specific composition of each tablet is summarized in Table 1 below.
In the examples and comparative examples, "Kimika algin I series I-8" manufactured by Kimika Co., Ltd. was used as sodium alginate.

Example 1: Release control tablet containing citric acid 1
A release controlled tablet containing mirabegron and an acidic pH regulator was produced. The medium diameter (D ₅₀ ) of mirabegron used in the following examples, comparative examples, and formulation examples was in the range of 13.0 μm to 14.4 μm. Mirabeglon, sodium alginate, citric acid hydrate, calcium chloride hydrate, polyethylene glycol 6000, and D-mannitol were placed in a polyethylene bag and mixed to obtain a mixture. Magnesium stearate was added to the mixture, mixed with a diffusion mixer, and then tableted (tablet pressure 12 kN) using a tabletop tablet molding machine (HANDTAB-100: Hitotsubashi Seiki Co., Ltd.) to obtain tablets.

Example 2: Release control tablet 2 containing citric acid
Mirabeglon, sodium alginate, citric acid hydrate, calcium chloride dihydrate, polyethylene glycol 6000, and hydroxypropyl cellulose (HPC-SL: Nippon Soda Co., Ltd.) are mixed in a polyethylene bag and mixed. Got Magnesium stearate was added to the mixture, and the mixture was mixed with a diffusion mixer and then tableted (tablet pressure 10 kN) using a tabletop tablet molding machine to obtain tablets.

Example 3: Release control tablet 3 containing citric acid
Tablets were produced in the same manner as in Example 1 except that the compositions of citric acid hydrate and polyethylene glycol 6000 in the tablets were changed.

Example 4: Release Controlled Tablets 1 Containing Carboxymethyl Cellulose
A release controlled tablet containing mirabegron and a water-insoluble disintegrant was produced. Mirabeglon, sodium alginate, carboxymethyl cellulose (NS300, Nichirin Chemical Industry Co., Ltd.), calcium chloride hydrate, polyethylene glycol 6000, and D-mannitol were placed in a polyethylene bag and mixed to obtain a mixture. Magnesium stearate was added to the mixture, and the mixture was mixed with a diffusion mixer and then tableted (tablet pressure 8 kN) using a tabletop tablet molding machine to obtain tablets.

Example 5: Release Controlled Tablets 2 Containing Carboxymethyl Cellulose
Mirabeglon, sodium alginate, carboxymethyl cellulose, calcium chloride dihydrate, polyethylene glycol 6000, and hydroxypropyl cellulose were placed in a polyethylene bag and mixed to obtain a mixture. Magnesium stearate was added to the mixture, and the mixture was mixed with a diffusion mixer and then tableted (tablet pressure 10 kN) using a tabletop tablet molding machine to obtain tablets.

Example 6: Release Controlled Tablets 3 Containing Carboxymethyl Cellulose 3
Tablets were produced in the same manner as in Example 4 except that the compositions of carboxymethyl cellulose and polyethylene glycol 6000 in the tablets were changed.

Example 7: Release Control Tablets Containing Calcium Carboxymethyl Cellulose Mirabeglon, Sodium Arginate, Calcium Carboxymethyl Cellulose (ECG-505, Nichirin Chemical Industry Co., Ltd.), Calcium Chloride Dihydrate, Polyethylene Glycol 6000, and Hydroxypropyl Cellulose And mixed in a polyethylene bag to obtain a mixture. Magnesium stearate was added to the mixture, and the mixture was mixed with a diffusion mixer and then tableted (tablet pressure 10 kN) using a tabletop tablet molding machine to obtain tablets.

Example 8: Release control tablet containing sodium starch glycolate Milabegron, sodium alginate, sodium starch glycolate (Primojel, DFE Pharma), calcium chloride dihydrate, polyethylene glycol 6000, hydroxypropyl cellulose and the like. Was placed in a polyethylene bag and mixed to obtain a mixture. Magnesium stearate was added to the mixture, and the mixture was mixed with a diffusion mixer and then tableted (tablet pressure 12 kN) using a tabletop tablet molding machine to obtain tablets.

Example 9: Release-controlled tablet containing citric acid and carboxymethyl cellulose A release-controlled tablet containing mirabegron, an acidic pH regulator, and a water-insoluble disintegrant was produced. Mirabeglon, sodium alginate, citric acid hydrate, calcium chloride hydrate, and dibutyl hydroxytoluene were placed in an impact crusher and pulverized to obtain pulverized powder. Mirabegron and sodium alginate were mixed with a diffusion mixer and then sieved with a stainless steel sieve to obtain double powder. Grinding powder, double powder, carboxymethyl cellulose, polyethylene glycol 6000, D-mannitol, and magnesium stearate are added to a diffusion mixer and mixed, and the mixture is mixed with a dry granulator (roller compactor FT-MINI:). In addition to Freund Sangyo Co., Ltd.), granulation was performed. The granulated particles were sized with a combil to obtain a tableted powder. This tableting powder was tableted (tablet pressure 11 kN) using a rotary tableting machine to obtain tablets.

Comparative Example: Release-controlled tablet containing no acidic pH regulator and water-insoluble disintegrant As a comparative tablet, a release-controlled tablet containing mirabegron but not containing an acidic pH regulator and water-insoluble disintegrant was produced. .. Mirabeglon, sodium alginate, calcium chloride dihydrate, polyethylene glycol 6000, and hydroxypropyl cellulose were placed in a polyethylene bag and mixed to obtain a mixture. Magnesium stearate was added to the mixture, and the mixture was mixed with a diffusion mixer and then tableted (tablet pressure 12 kN) using a tabletop tablet molding machine to obtain tablets.

As shown in Table 1 above, the tablets of Examples 1 to 3 are examples of tablets using an acidic pH adjuster, and Examples 4 to 8 are examples of tablets using a water-insoluble disintegrant. Example 9 is an example of producing a tablet using both an acidic pH adjuster and a water-insoluble disintegrant. The following tests were performed using these tablets.

[Examination of tablet disintegration time]
The disintegration time was measured according to the disintegration test method described in the 17th revised Japanese Pharmacopoeia. Water (900 mL) was used as the test solution, and after the tablets were put into the disintegration test device, the basket containing the tablets (the bottom was reticulated) was moved up and down in the water of the container and stirred. The measurement was continued until no sample was found in the test device, and that time was taken as the disintegration time of the tablet. The disintegration time of the tablets was measured for the tablets of Comparative Example, Example 2, Example 5, Example 7 and Example 8, and the results are shown in Table 2.

From Table 2, by producing a tablet by adding an acidic pH adjuster or a water-insoluble disintegrant, the disintegration time becomes longer as compared with the comparative example tablet containing no acidic pH adjuster or water-insoluble. It was shown to be.

[Examination of tablet elution]
According to the dissolution test method (method 2) described in the 17th revised Japanese Pharmacopoeia, the rotation speed of the paddle was set to 50 rpm, and water (900 mL) was used as the test solution in Examples 1 to 9 and Comparative Examples. A tablet dissolution test was performed. The test solution was collected 0 minutes, 30 minutes, 60 minutes, 180 minutes, 300 minutes, 420 minutes, 540 minutes, and 720 minutes after the start of the test, and the drug concentration was measured with a spectrophotometer. The test was performed on 2 tablets, and the average value of the dissolution rate was calculated.

The measurement results for the dissolution property are shown in FIGS. 1 to 4, respectively. FIG. 1 shows the measurement results of the tablets of Comparative Example, Example 2, Example 5, Example 7, and Example 8. FIG. 2 shows the tablet measurement results of Example 9. FIG. 3 shows the measurement results of the tablets of Comparative Example, Example 1, Example 2, and Example 3. FIG. 4 shows the measurement results of the tablets of Comparative Example, Example 4, Example 5, and Example 6. From FIGS. 1 to 4, the tablet of Comparative Example had an elution rate of almost the maximum value at 420 minutes, whereas the tablet of Example had a dissolution rate of 540 minutes or later. Therefore, by producing a tablet by adding an acidic pH adjuster or a water-insoluble disintegrant, the dissolution rate is lower than that of the comparative example tablet containing no acidic pH adjuster or water-insoluble disintegrant. It was suppressed. For example, the time it takes for mirabegron released from tablets to reach maximum concentrations has been extended. Thus, it was shown that sustained release was improved.

(Prescription example)
Examples of tablet production are shown in Table 3 below. Granulation and tableting can be manufactured, for example, as follows.

1) Sodium alginate (I-8, Kimika), calcium chloride hydrate, citric acid hydrate and dibutyl hydroxytoluene are roughly mixed in a polyethylene bag and crushed with an impact crusher to obtain crushed powder.
2) After mixing mirabegron and sodium alginate in a diffusion mixer, sieve through a stainless steel sieve to obtain double powder.
3) The above pulverized powder, double-dispersed powder, polyethylene glycol 6000, D-mannitol, carbosikimethylcellulose, and magnesium stearate are mixed with a diffusion mixer to obtain a mixture.
4) Add the mixture to a dry granulator and granulate to obtain particles.
5) Granulate the granulated particles with a dry granulator (Quadrocomil QC-197S: Paulek Co., Ltd.) to obtain a tableted powder.
6) The tableting powder is tableted using a rotary tableting machine to obtain a tablet.

When the tablet diameter, tablet thickness and hardness of the obtained tablets were measured, the tablet diameter was 12.0 × 6.0 mm, the tablet thickness was 4.4 mm, and the hardness was 116 N. The tablet thickness refers to the length from the apex of the ridge on the upper surface to the apex of the ridge on the lower surface of the manufactured tablet, and was measured using a dial thickness gauge (Ozaki Seisakusho). The lock diameter was measured using a dial thickness gauge in the same manner as the lock thickness. The hardness was measured by using an ERWEKA type tablet hardness tester (TBH425TD: ERWAKA) and applying a load to the tablet with an indenter by an electric weight load.

Claims (12)

A release-controlled tablet comprising at least one of an acidic pH regulator and a water-insoluble disintegrant, alginate, and Mirabeglon or a pharmaceutically acceptable salt thereof or a solvate thereof. The release-controlled tablet according to claim 1, which comprises an acidic pH adjuster and a water-insoluble disintegrant. The release-controlled tablet according to claim 1 or 2, wherein the content of the alginate is 25% by mass or more and 60% by mass or less of the total mass of the tablet. The release-controlled tablet according to any one of claims 1 to 3, wherein the alginate is sodium alginate. The release-controlled tablet according to any one of claims 1 to 4, wherein the acidic pH adjuster is 1% by mass or more and 25% by mass or less of the total mass of the tablet. The release-controlled tablet according to any one of claims 1 to 5, wherein the acidic pH adjuster is an organic acid or a salt thereof. The release-controlled tablet according to any one of claims 1 to 6, wherein the acidic pH regulator is at least one selected from citric acid, L-aspartic acid, ascorbic acid, or a salt thereof. The release-controlled tablet according to any one of claims 1 to 7, wherein the water-insoluble disintegrant is 1% by mass or more and 25% by mass or less of the total mass of the tablet. The release-controlled tablet according to any one of claims 1 to 8, wherein the water-insoluble disintegrant is at least one selected from carboxymethyl cellulose, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose or sodium starch glycolate. A step of obtaining a mixture containing at least one of an acidic pH regulator and a water-insoluble disintegrant, alginate, and mirabegron or a pharmaceutically acceptable salt thereof or a solvate thereof.
The process of granulating the mixture to obtain granulated products and
A method for producing a release-controlled tablet containing mirabegron or a pharmaceutically acceptable salt thereof or a solvate thereof, which comprises a step of compression-molding the granulated product to obtain a tablet. The production method according to claim 10, wherein the mixture comprises the acidic pH adjuster and the water-insoluble disintegrant. Mirabeglon from the tablet by incorporating at least one of an acidic pH regulator and a water-insoluble disintegrant and alginate in a tablet containing Mirabeglon or a pharmaceutically acceptable salt thereof or a solvate thereof. How to control the release of.

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