KR102546923B1 - Controlled-released dosage form comprising mirabegron as an active ingredient - Google Patents

Abstract

The present invention relates to a controlled-release formulation of mirabegron, and can provide a controlled-release formulation containing a hydrogel-forming polymer and a hydrophilic base for controlling the release of mirabegron, and having improved stability.

Description

Controlled release formulation containing mirabegron {CONTROLLED-RELEASED DOSAGE FORM COMPRISING MIRABEGRON AS AN ACTIVE INGREDIENT}

Cross-Citation with Related Applications

The present invention claims the benefit of priority based on Korean Patent Application No. 10-2020-0026553 filed on March 3, 2020, and includes all contents disclosed in the literature of the Korean patent application as part of this specification.

technology field

The present invention relates to a controlled release formulation comprising mirabegron or a pharmaceutically acceptable salt thereof as a main component. More specifically, it is intended to provide a controlled-release preparation containing mirabegron, a hydrogel-forming polymer that controls the release of mirabegron, and a hydrophilic base, and having improved stability.

Overactive bladder is defined as the presence of urinary urgency, with or without urgency urinary incontinence, in the absence of urinary tract infection and no other apparent etiology, and is often accompanied by daytime and nocturia. Mirabegron is (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetic acid anilide for overactive bladder is used in the treatment of

Korean Patent Registration No. 10-1524164 discloses a controlled-release pharmaceutical composition containing mirabegron as a main component. In this patent, (1) mirabegron or a pharmaceutically acceptable salt as a main component, (2) one or more additives for infiltrating water into a solubility formulation in which the amount of water to dissolve 1 g is 10 mL or less, and (3) Disclosed is a controlled-release pharmaceutical composition comprising a polymeric substance forming a hydrogel having an average molecular weight of about 100,000 or more or a 5% aqueous solution having a viscosity of 12 mPa·s or more at 25°C. In the examples of this patent, polyethylene glycol (PEG) is exemplified as an additive for infiltrating water into the formulation, and polyethylene oxide (PEO) is exemplified as a hydrogel forming polymer material. As a polymer, there is a high risk of reacting with mirabegron to generate related substances or changing the dissolution rate due to changes in physical properties. Korean Patent Registration No. 10-1937713 discloses a controlled-release formulation containing mirabegron as an active ingredient and PEO as a release-controlling agent and not including an additive for infiltrating water into the formulation. However, since this patent also uses PEO as a release-controlling polymer, it still includes the above problems.

Republic of Korea Patent Registration No. 10-2062791 discloses a technical idea in which mirabegron is used as a main component, PEO is used as a release control agent, and isomalt is used as a hydrophilic base. However, this patent also does not recognize the generation of related substances of Mirabegron by the use of PEO.

Korean Patent Registration No. 10-2051132 includes mirabegron or a pharmaceutically acceptable salt thereof as an active ingredient, 300,000 polyethylene oxide (PEO) and 1 million polyethylene oxide (PEO) as a sustained release agent, and a hydrophilic agent Disclosed is a pharmaceutical composition for controlled release, characterized in that it does not contain polyethylene glycol (PEG). This patent also only discloses a technical idea that does not include a hydrophilic base, and does not recognize the stability problem of Mirabegron by PEO.

Korean Patent Laid-open Publication No. 10-2019-0089758 discloses the use of PEO as a controlled-release agent and polyvinyl alcohol as a fast-acting excipient. This patent also does not recognize that PEO affects the stability of mirabegron.

Korean Patent Publication No. 10-2019-0117072 discloses a controlled-release pharmaceutical composition characterized in that a polymer material and a gum are used in combination to form a hydrogel. In this patent, when PEO is used as a sustained release agent, it recognizes the problem that bursting of the drug may occur during the stability period due to polymer chain degradation due to photolysis and oxidation, but does not specifically exemplify sodium alginate. there is.

Korean Patent Publication No. 10-2017-0088783 discloses a granular composition containing mirabegron, characterized in that it contains polyethylene oxide and a silicate compound to improve productivity. This patent is intended to solve the problems that occur when granulating mirabegron and PEO in a high shear mixer through the addition of silicate, and does not disclose the technical idea that PEO should be replaced.

Korean Patent Publication No. 10-2018-0106924 discloses a controlled-release pharmaceutical composition containing mirabegron and PEO having a specific viscosity and content as a release-controlling substance. Even in this patent, the problem of mirabegron stability by PEO is not recognized.

Republic of Korea Patent No. 10-1524164 Republic of Korea Patent No. 10-1937713 Republic of Korea Patent No. 10-2062791 Republic of Korea Patent No. 10-2051132 Republic of Korea Patent Publication No. 10-2019-0089758 Republic of Korea Patent Publication No. 10-2019-0117072 Republic of Korea Patent Publication No. 10-2017-0088783 Republic of Korea Patent Publication No. 10-2018-0106924

As reviewed above, it can be seen that PEO is used in the controlled release of mirabegron in the prior invention. However, PEO and mirabegron have problems in miscibility and stability during storage, and therefore, the formulations described in the prior art inevitably have quality problems due to reduced stability including increased related substances. In the present invention, in order to solve the stability problem, it is a technical problem to solve the problem of finding a means capable of controlling the release of mirabegron without using PEO.

As a means to solve the above technical problem, in the present invention, hydroxyethyl cellulose (HEC) is adopted as a controlled release polymer, and at the same time, alginic acid, a salt of alginic acid or an alginic acid derivative is added thereto, thereby increasing the stability while increasing the desired A controlled release formulation of mirabegron having a release pattern is disclosed.

According to the present invention, the controlled-release formulation of mirabegron suppresses generation of related substances through improved stability, exhibits a stable release pattern, and provides an effect of improving productivity.

1 shows a dissolution graph of a comparative example and a controlled-release formulation according to the present invention at pH 6.8.
Figure 2 shows a dissolution graph of the comparative example and the controlled-release formulation according to the present invention at pH 1.2.
Figure 3 shows the change in properties after the harsh test by mixing mirabegron with additives used in the prior art or additives used in the present invention.
Figure 4 shows the change in properties after the harsh test of the comparative example and the controlled-release formulation according to the present invention.

While the inventors of the present invention were researching and developing a formulation for controlling the release of mirabegron, it was confirmed that polyethylene oxide (PEO), a conventionally widely used polymer, reacts with mirabegron to generate related substances. Excessive production of these related substances has a problem in that the content of mirabegron, the main ingredient, may decrease and the efficacy of the drug may decrease over time. Furthermore, PEO having a high molecular weight of 1 million or more and high viscosity may be exposed to high temperatures for a period of time. It was confirmed that there was a problem in that the initial viscosity could not be maintained due to decomposition over time and the controlled dissolution characteristics could not be maintained. In addition, it was confirmed that the viscosity of PEO is lowered in a high temperature and high humidity environment, causing a change in properties, and when PEO and mirabegron are formulated into granules, non-uniform aggregates are generated. That is, when using PEO, stability and quality problems arise in related substances, efficacy, properties, dissolution, etc., and in the present invention, it has been changed to a hydrogel forming polymer.

In addition, according to the prior art, PEGs, sugars, and sugar alcohols used as additives (hereinafter referred to as 'hydrophilic bases') for infiltrating water into the formulation together with the hydrogel-forming polymer in order to control-release mirabegron. Also, it was confirmed that there is a problem of reacting with Mirabegron to generate related substances. In addition, sugar alcohols have reducing sugars, so they react with amino groups present in Mirabegron, causing a Maillard reaction. It was confirmed that there is a risk of doing so.

Thus, the inventors of the present invention selected a hydrogel-forming polymer as an alternative to PEO as a release-controlling polymer, and selected alginic acid and its salt as an alternative to a hydrophilic base to complete the present invention.

controlled release formulation

The present invention relates to mirabegron or a pharmaceutically acceptable salt; a hydrogel-forming polymer as a release-controlling polymer; and alginic acid or a salt thereof as a hydrophilic base.

In the present invention, the term "controlled-release preparation" means a preparation in which the active ingredient is released in the body over a long period of time.

In the present invention, the term “main ingredient” refers to mirabegron, which is the most important factor in controlled-release preparations, and the formula (R)-2-(2-aminothiazol-4-yl)-4′-[2-[ (2-Hydroxy-2-phenylethyl)amino]ethyl]acetic acid anilide, which is meant to be used in the treatment of overactive bladder.

In the present invention, the term "pharmaceutically acceptable" means that it is physiologically acceptable and does not usually cause allergic reactions such as gastrointestinal disorders and dizziness or similar reactions when administered to humans. In this case, the term "salt" is an acid addition salt formed by an acceptable free acid, and refers to a salt prepared according to a conventional method, and the method for preparing such a pharmaceutically acceptable salt is not available to those skilled in the art. It is known. Pharmaceutically acceptable salts include, for example, inorganic ion salts prepared with calcium, potassium, sodium and magnesium, inorganic acid salts prepared with hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, iodic acid, hydroiodic acid, perchloric acid and sulfuric acid. , acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucu Organic acid salts made of ronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, etc., sulfonic acid salts made of methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and naphthalenesulfonic acid, glycine, There are amino acid salts made of arginine, lysine, etc., and amine salts made of trimethylamine, triethylamine, ammonia, pyridine, picoline, etc., but the types of salts meant in the present invention are limited by these salts. no.

In the present invention, the term "release-controlled polymer" refers to a substance used to release mirabegron or a pharmaceutically acceptable salt over a long period of time.

In the present invention, the term "hydrogel-forming polymer" refers to a polymer capable of forming a three-dimensional network formed of hydrophilic polymer chains in an environment in which water is sufficiently present as a sustained-release agent, and can control-release mirabegron. Means a polymer that can

In the present invention, the hydrogel-forming polymer may be at least one selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose and methyl cellulose, preferably hydroxy It may be ethyl cellulose, hydroxypropyl cellulose or a combination of hydroxyethyl cellulose and hydroxypropyl cellulose, more preferably a combination of hydroxyethyl cellulose and hydroxypropyl cellulose, but is not limited thereto. Specifically, when using a combination of hydroxyethyl cellulose and hydroxypropyl cellulose as a hydrogel-forming polymer, problems occurring when using a specific polymer such as polyethylene oxide (PEO) (generation of related substances due to reaction with mirabegron, stability reduction, physical property change, dissolution reduction, efficacy reduction, etc.) can be improved, and release control of mirabegron can be easily controlled.

In the case of a combination of hydroxyethyl cellulose and hydroxypropyl cellulose, they may be combined in a weight ratio of 3 to 10: 1, and more preferably in a weight ratio of 5 to 8: 1, but are not limited thereto.

In the present invention, the weight average molecular weight (Da) of the hydrogel-forming polymer may be 90,000 to 720,000, but is not limited thereto.

In the present invention, the term "alginic acid or its salt" means a hydrophilic base for infiltrating water into the formulation together with the hydrogel-forming polymer, and the salt of alginic acid may be sodium alginate, but is not limited thereto. .

Specifically, the inventors of the present invention used alginic acid and its salts instead of PEGs, sugars, and sugar alcohols conventionally used as hydrophilic bases. Mirabegron or a pharmaceutically acceptable salt thereof is a basic drug and exhibits high solubility at low pH and low solubility at high pH (pKa of about 4.0). On the other hand, hydrogel-forming polymers are hydrolyzed at low pH, and the release control properties are weakened. Therefore, alginic acid or sodium alginate was selected as an additive to adjust the dissolution rate at low pH equal to that of the reference drug. In particular, sodium alginate is changed to insoluble alginate in organic solvents and aqueous acidic solutions with a pH of less than 3 to form a release barrier and prevent initial burst. At the same time, sodium alginate is ionized at high pH to form a water-soluble gel, releasing the drug by diffusion/erosion. has the characteristic of

That is, in the present invention, the agent capable of controlling the release of mirabegron can achieve the task by combining hydroxyethyl cellulose, which is a hydrogel-forming polymer, and alginic acid or a salt thereof, which is a hydrophilic base.

In the present invention, the term "combination" means one or more components that are combined but not mixed.

In the present invention, the viscosity of the alginate may be 15 to 450 cP, but is not limited thereto.

In the present invention, the term "viscosity" means that it is measured according to the Korean Pharmacopoeia viscosity measurement method, and the unit is cP (Centi poise).

In the present invention, the mirabegron or pharmaceutically acceptable salt may include 15 to 30% by weight, preferably 20 to 25% by weight based on the weight of the total controlled-release preparation. It may include, but is not limited to.

In the present invention, the release-controlling polymer may include an amount of 20 to 50% by weight, preferably 35 to 45% by weight based on the weight of the total release-controlling formulation, limited thereto. it is not going to be

In the present invention, the hydrophilic base may include an amount of 1 to 40% by weight, preferably 1.5 to 25% by weight based on the weight of the total release-controlled formulation, It is not.

Specifically, if the release-controlling polymer and the hydrophilic base are out of the above ranges, the dissolution rate of mirabegron from the formulation may be excessively reduced or accelerated, making it difficult to ensure a target release rate.

In the present invention, the controlled-release preparation may be one that does not contain polyethylene oxide essentially, and may also be one that does not essentially contain polyethylene glycols, sugars and sugar alcohols, but is not limited thereto.

Specifically, what is essentially not included in the controlled-release formulation of the present invention is polyethylene glycol; sugars such as lactose, white sugar, anhydrous maltose, D-fructose, dextran, and glucose; sugar alcohols such as D-mannitol, D-sorbitol, and xylitol; It may be gums such as xanthan gum, gum arabic, locust bean gum, guar gum, and gellan gum, but is not limited thereto.

In the present invention, the term “essentially free” means not containing a predetermined component at all.

The controlled-release formulation of the present invention does not use polyethylene oxide as a hydrogel-forming polymer and does not use PEGs, sugars, sugar alcohols, or gums as a hydrophilic base, thereby suppressing the generation of related substances through improved stability and providing stable It shows a release pattern and can improve productivity.

In the present invention, the controlled-release formulation may further contain pharmaceutically acceptable additives, commonly used suitable carriers, excipients, disintegrants, binders, lubricants or diluents.

In the present invention, the term "pharmaceutically acceptable additive" includes carriers, excipients, disintegrants, binders, lubricants or diluents that do not inhibit the biological activity and properties of the injected compound without stimulating the living organism. can do. The type of the additive that can be used in the present invention is not particularly limited, and any additive commonly used in the art and pharmaceutically acceptable may be used. Non-limiting examples of the additive may include microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, colloidal silicon dioxide, magnesium stearate, or mixtures thereof.

In the present invention, the controlled-release formulation is mirabegron or a pharmaceutically acceptable salt is 3 in the dissolution test (37 ℃, pH 6.8, 900 mL, 50 rpm) according to the dissolution test method 2 (paddle method) of the Korean Pharmacopoeia. It may be 25 to 45% in time, 50 to 70% in 5 hours, and 75% or more in 8 hours, and more specifically, the controlled release agent is released in the dissolution test according to the Korean Pharmacopoeia Dissolution Test Method 2 (paddle method) (37°C, pH 6.8, 900 mL, 50 rpm) 30 to 42% of mirabegron or a pharmaceutically acceptable salt may be released in 3 hours, 50 to 65% in 5 hours, and 80% or more in 8 hours. Yes, but not limited thereto. Through the above information, the controlled-release formulation of the present invention may exhibit a dissolution rate similar to that of commercially available beta-miga sustained-release tablets.

In the present invention, the controlled-release formulation is mirabegron or a pharmaceutically acceptable salt is 15% in the dissolution test (37 ℃, pH 1.2, 900 mL, 50 rpm) according to the dissolution test method 2 (paddle method) of the Korean Pharmacopoeia. It may be 5 to 15% in minutes, 18 to 25% in 45 minutes, and 27% or more in 90 minutes, and more specifically, the controlled release agent is dissolution test according to the Korean Pharmacopoeia Dissolution Test Method 2 (paddle method) (37° C., pH 1.2, 900 mL, 50 rpm) 8 to 12% of mirabegron or a pharmaceutically acceptable salt may be released at 15 minutes, 20 to 25% at 45 minutes, and 30% or more at 90 minutes. Yes, but not limited thereto.

By dissolving mirabegron or a pharmaceutically acceptable salt as described above, the controlled-release formulation of the present invention can prevent the dissolution burst of the drug at low pH and exhibit a dissolution rate similar to that of commercially available betami sustained-release tablets. there is.

Method for producing controlled-release formulations

The present invention comprises the steps of (S1) preparing a mixture by mixing mirabegron or a pharmaceutically acceptable salt, a release-controlling polymer, a hydrophilic base and pharmaceutically acceptable additives; (S2) preparing granules by adding ethanol to the mixture of (S1), mixing, and then drying; and (S3) tableting the granules of (S2).

In the present invention, the term "mixture" means a blend of one or more components, wherein the components can interact at the molecular level, for example, a homogeneous mixture is a mixture in which the components are uniform and homogeneous A heterogeneous mixture is a mixture in which the components are uniformly and non-homogeneously distributed, whereas a heterogeneous mixture is a mixture in which the components are uniformly and non-homogeneously distributed.

In the present invention, the controlled-release preparation may be prepared by wet granulation, direct tableting or dry granulation, preferably by wet granulation, but is not limited thereto.

The formulation according to the present invention can be prepared through a conventional assembly method known in the art. For example, it can be prepared by mixing and tableting appropriate carriers, excipients, diluents, binders, etc. commonly used in the preparation of formulations.

Such carriers, excipients and diluents include gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc , magnesium stearate and mineral oil. The binder may include at least one selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose, dextrin, gelatin, methylcellulose, hydroxymethylcellulose, and polyvinyl alcohol. In addition, various pharmaceutically acceptable additives may be appropriately added to the controlled-release preparation of the present invention to be formulated into any pharmaceutical preparation. These additives are pharmaceutically acceptable and pharmacologically acceptable, and any additives may be used within the range not impairing the object of the present invention. Additives may include disintegrants, lubricants, colorants, surfactants, stabilizers, and the like, and are not particularly limited thereto. Examples of the disintegrant include crospovidone, carmellose calcium, carmellose sodium, and low-substituted hydroxypropyl cellulose. Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, talc, and stearic acid.

Matters mentioned in the controlled-release formulation of the present invention and the manufacturing method thereof are equally applied unless contradictory to each other.

Hereinafter, preferred embodiments are presented to aid understanding of the present invention, but the following examples are merely illustrative of the present invention, and various changes and modifications are possible within the scope and spirit of the present invention, and such changes and modifications Specific aspects also belong to the scope of the present invention.

Example

preparation of materials

Materials used in the following examples were purchased and prepared from Ashland, DFE, etc.

Example 1

50 g of mirabegron, 81 g of hydroxyethyl cellulose (HEC), 46 g of alginic acid, 39 g of microcrystalline cellulose, and 11.5 g of hydroxypropyl cellulose were mixed in a mixer for 10 minutes, and then kneaded using 100 g of ethanol and kneaded at 60 ° C. dried. The dried granules were sized through a 20 mesh sieve, and 2.5 g of magnesium stearate was added and mixed for 5 minutes. Then, the mixture was tableted to prepare a controlled-release formulation.

Examples 2 to 6

In the same manner as in Example 1, a controlled-release formulation was prepared by varying the weight average molecular weight of hydroxyethyl cellulose and the type of alginate or sodium alginate as a hydrophilic base.

Each component and content included in the controlled-release formulations of Examples 1 to 6 are shown in Table 1 below.

[Table 1]

Examples 7 to 11

In the same manner as in Example 1, a controlled release formulation was prepared by varying the viscosity of sodium alginate and the content of each component.

Each component and content included in the controlled-release formulations of Examples 7 to 11 are shown in Table 2 below.

[Table 2]

Comparative Examples 1 to 4

In Comparative Example 1, a commercially available betamiga sustained-release tablet was used. Comparative Examples 2 to 4 were prepared in the same manner as in Example 1, with different types and contents of each additive.

Each component and content included in the formulations of Comparative Examples 2 to 4 are shown in Table 3 below.

[Table 3]

Experimental example

Experimental Example 1: Dissolution Test 1

For the above Examples and Comparative Examples, a dissolution test was performed according to the Korean Pharmacopoeia Dissolution Test Method 2 (paddle method). As the test solution, 900 mL of pH 6.8 (the second liquid of the disintegration test method of the Korean Pharmacopoeia) was used, and the test was performed using a sinker under conditions of 37 ° C. and a paddle rotation of 50 rpm. The results are shown in Table 4 and FIG. 1 below.

[Table 4]

As shown in Table 4 and FIG. 1, it was confirmed that Examples 3, 8, and 11 showed a similar level of dissolution as Comparative Example 1 (commercially available beta-miga sustained-release tablet).

Experimental Example 2: Dissolution test 2

For the above Examples and Comparative Examples, a dissolution test was performed according to the Korean Pharmacopoeia Dissolution Test Method 2 (paddle method). As the test solution, 900 mL of pH 1.2 (Korean Pharmacopoeia disintegration test method 1st solution) was used, and the test was performed using a sinker under conditions of 37 ° C. and a paddle rotation of 50 rpm. The results are shown in Table 5 and FIG. 2 below.

[Table 5]

As shown in Table 5 and FIG. 2, Comparative Example 3, which does not contain a hydrophilic base such as alginate or sodium alginate, loses sustained release due to hydrolysis of the hydrogel at low pH, and it can be confirmed that dissolution burst occurs. This means that the desired drug effect cannot be exerted in vivo and the risk of causing side effects is very high. On the other hand, as in Example 8, when a polymeric material forming a hydrogel as a sustained-release agent and sodium alginate as a hydrophilic base are used together, dissolution burst of the drug is prevented at low pH and a dissolution rate similar to that of the control drug (Comparative Example 1) is obtained. It could be seen that the indicated

Experimental Example 3: Related substance production test

The hydrophilic base (PEG 8000) used in the prior art, the hydrogel-forming polymer (PEO), and the hydrogel-forming polymer (HEC) used in the present invention were mixed with mirabegron, the main ingredient, respectively, and then subjected to harsh conditions (70 ° C, Relative humidity of 90%) was tested for 1 week to observe changes in related substances, and the results are shown in Table 6 and FIG. 3 below.

[Table 6]

As shown in Table 6, in the case of the additives used in the prior art, it was confirmed that up to 13 times more related substances were produced when reacted with mirabegron compared to the HEC used in the present invention. Likewise, it was confirmed that the change in appearance was also very severe. On the other hand, it was confirmed that the present invention has very little interaction with the main component, so that related substances are less generated and very stable with almost no change in properties.

Experimental Example 4: Stability test

The Example 11 and Comparative Example 1 were packaged in wrapping paper, and the change in properties after storage at 80 ° C. for 6 hours was confirmed in consideration of the harsh storage conditions in summer. As shown in Figure 4, in the case of Example 11 (a controlled-release formulation using hydroxyethyl cellulose and sodium alginate as a sustained-release agent), no change in properties was observed with storage, but Comparative Example 1 had a melting point of 67 ° C. As the phosphorus PEO melted and condensed, it was clearly confirmed that the tablet initially composed of opaque white particles was changed to a translucent pale yellow glassy form. Since these changes have already been revealed in the prior art, it was confirmed that there is a risk of causing a change in product quality even in a short time.

The mirabegron controlled-release preparation according to the present invention shows a stable drug release pattern without deterioration in stability including generation of related substances, and has excellent productivity.

Claims (8)

Mirabegron or a pharmaceutically acceptable salt;
A combination of hydroxyethyl cellulose and hydroxypropyl cellulose, which are hydrogel forming polymers, as a release-controlling polymer; and
A controlled-release formulation comprising alginic acid or sodium alginate having a viscosity of 15 to 450 cP as a hydrophilic base,
Mirabegron or a pharmaceutically acceptable salt is included in an amount of 15 to 30% by weight based on the weight of the total controlled-release preparation,
The release-controlling polymer is to include a content of 20 to 50% by weight based on the weight of the total release-controlling formulation,
The controlled-release formulation comprising the hydrophilic base in an amount of 1 to 40% by weight based on the total weight of the controlled-release formulation. delete delete delete delete According to claim 1,
In the dissolution test (37 ℃, pH 6.8, 900 mL, 50 rpm) according to the dissolution test method 2 (paddle method) of the Korean Pharmacopoeia, 25 to 45% of mirabegron or a pharmaceutically acceptable salt in 3 hours, 5 hours 50 to 70%, 75% or more in 8 hours to release the controlled-release formulation. According to claim 1,
In the dissolution test (37℃, pH 1.2, 900 mL, 50 rpm) according to the Dissolution Test Method 2 (paddle method) of the Korean Pharmacopoeia, 5 to 15% of mirabegron or a pharmaceutically acceptable salt in 15 minutes, 45 minutes 18 to 25%, 27% or more is released in 90 minutes. (S1) Mirabegron or a pharmaceutically acceptable salt, hydroxyethyl cellulose and hydroxypropyl cellulose, which are hydrogel forming polymers as release-controlling polymers, alginic acid or sodium alginate having a viscosity of 15 to 450 cP as a hydrophilic base, and drugs preparing a mixture by mixing chemically acceptable additives;
(S2) preparing granules by adding ethanol to the mixture of (S1), mixing, and then drying; and
(S3) tableting the granules of (S2)
Including,
In the step (S1), mirabegron or a pharmaceutically acceptable salt is included in an amount of 15 to 30% by weight based on the weight of the total release-controlled formulation, and the release-controlled polymer is the weight of the total release-controlled formulation. 20 to 50% by weight based on the content, the hydrophilic base is the release of claim 1 comprising the step of mixing to include the content of 1 to 40% by weight based on the weight of the total controlled-release formulation Methods for preparing controlled formulations.

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