KR20190089758A - Sustained-release preparation containing mirabegron or pharmaceutically acceptable salt thereof - Google Patents

Abstract

The present invention relates to a sustained-release preparation containing mirabegron or a pharmaceutically acceptable salt thereof, wherein the controlled-release pharmaceutical composition according to the present invention has a high dissolution rate in water of the active ingredient mirabegron, This has an excellent effect.
Further, there is an effect of hardly generating a flexible material under accelerated conditions, less change in properties of a static material, and excellent in content stability.

Description

[0001] The present invention relates to a sustained-release preparation containing mirabegron or a pharmaceutically acceptable salt thereof,

The present invention relates to a sustained-release preparation containing mirabegron or a pharmaceutically acceptable salt thereof, and more particularly to a preparation having improved solubility and stability in water.

Mirabegron is a drug that selectively acts on the β3-adrenergic receptor to treat overactive bladder. Its chemical name is (R) -2- (2-aminothiazol-4-yl) -4 ' [(2-hydroxy-2-phenylethyl) amino] ethyl} acetanilide.

In particular, mirabegron can be used as a therapeutic agent for overactive bladder by acting on the? 3-adrenergic receptor to increase bladder storage ability through bladder relaxation, and can be used as an overactive bladder, urinary urgency, urinary incontinence or urinary frequency It has been reported to be useful as a therapeutic agent for the accompanying overactive bladder.

However, Mirabegron is a water-insoluble, poorly soluble component. As a result of conducting a clinical trial using a pharmaceutical preparation, unexpectedly, pharmacokinetic data largely changed in the presence or absence of diets. For example, the reduction rate of Cmax and predicting AUC were 63% and 47%, respectively, compared to that under fasting, and the Cmax at fasting was three times higher than that at predation.

As such, Mirabegron greatly changes the pharmacokinetic properties depending on whether or not food is consumed, and development of a formulation for avoiding such influence is required.

In this regard, Korean Patent No. 10-1524164 discloses a pharmaceutical composition containing Mirabegron or a pharmaceutically acceptable salt thereof, an additive for invading water into the preparation, and a hydrogel-forming polymeric material, Controlled pharmaceutical composition which reduces the fluctuation of AUC or Cmax due to dietary intake has been disclosed.

However, in the pharmaceutical preparations containing mirabegron, there is a continuing need to develop a pharmaceutical composition which not only controls the release rate but also has improved solubility in water and stability of formulation of mirabegron, which has low solubility in water have.

Korean Patent Registration No. 10-1524164

Disclosure of Invention Technical Problem [8] Accordingly, the present invention has been made keeping in mind the above problems occurring in the prior art, and an object of the present invention is to provide a pharmaceutical composition comprising mirabegron or a pharmaceutically acceptable salt thereof as an active ingredient, To provide a sustained-release preparation having improved formulation stability and content uniformity, with little dissolution of the flexible material while improving the dissolution rate of the acceptable salt in water.

In order to achieve the above object, the present invention provides a pharmaceutical composition comprising an active ingredient, a short-acting polymer excipient and a release-controlling agent containing mirabegron or a pharmaceutically acceptable salt thereof,

Wherein the quick-acting polymeric excipient comprises polyvinyl alcohol,

Wherein the release control agent comprises at least one selected from the group consisting of a water-soluble polymer, a hydrophobic base, and a water-insoluble base.

The water-soluble polymer may be at least one selected from the group consisting of polyethylene oxide, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose sodium, hydroxyethylcellulose, and carboxyvinyl polymer.

The hydrophobic base is at least one selected from the group consisting of C ₈ to C ₂₆ fatty acids, C ₈ to C ₅₀ fatty acid esters, C ₆ to C ₃₀ higher alcohols, hydrogenated vegetable oils, hardened castor oil, and wax .

The water-insoluble base may be any one selected from the group consisting of polyvinylpyrrolidone-vinyl acetate, polyvinylpyrrolidone-vinyl acetate copolymer and ethylcellulose.

In addition, the controlled-release pharmaceutical composition according to the present invention further comprises at least one excipient selected from the group consisting of colloidal silicon dioxide, silicon dioxide, microcrystalline cellulose, lactose, corn starch, potassium hydrogen phosphate and pregelatinized starch .

Furthermore, the controlled-release pharmaceutical composition according to the present invention may further include at least one lubricant selected from the group consisting of stearate, glyceryl behenate, talc and silicon dioxide.

The release-controlled medicinal composition may include 10 to 1000 parts by weight of the quick-release polymer excipient per 100 parts by weight of the active ingredient.

The release control agent may be contained in an amount of 1 to 500 parts by weight based on 100 parts by weight of the active ingredient.

Further, the polyvinyl alcohol may be characterized in that the 5 wt% aqueous solution has a viscosity of 2 to 10 mPa · s at 25 ° C.

The controlled-release pharmaceutical composition according to the present invention has a high dissolution rate in water of mirabegron, which is an active ingredient, and has an excellent content uniformity.

Further, there is an effect of hardly generating a flexible material under accelerated conditions, less change in properties of a static material, and excellent in content stability.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows the results of Experimental Example 2 comparing the dissolution rates of water in the water of the controlled-release pharmaceutical composition of Mirabegron.
FIG. 2 shows the results of Experimental Example 5 in which changes in the properties of the preparations prepared from the controlled-release pharmaceutical composition containing Mirabegron were observed.

Hereinafter, the present invention will be described in detail. The terms and words used in the present specification and claims should not be construed as limited to ordinary or dictionary meanings and the inventor may properly define the concept of the term to describe its invention in the best possible way It should be construed as meaning and concept consistent with the technical idea of the present invention.

The present invention includes an effective ingredient, a short-acting polymer excipient and a release-controlling agent containing mirabegron or a pharmaceutically acceptable salt thereof,

Wherein the quick-acting polymeric excipient comprises polyvinyl alcohol,

Wherein the release control agent comprises at least one selected from the group consisting of a water-soluble polymer, a hydrophobic base, and a water-insoluble base.

First, the controlled-release pharmaceutical composition according to the present invention contains mirabegron or a pharmaceutically acceptable salt thereof as an active ingredient.

The mirabegron is a drug that selectively acts on the? 3-adrenergic receptor to treat overactive bladder. The chemical name is (R) -2- (2-aminothiazol-4-yl) - [(2-hydroxy-2-phenylethyl) amino] ethyl} acetanilide.

The mirabegron may be used in the form of a pharmaceutically acceptable salt. As the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful.

The acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid and the like, aliphatic mono- and dicarboxylates, phenyl- substituted alkanoates, hydroxyalkanoates and alkanes Such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, pyruvic acid, benzoic acid, citric acid, lactic acid, maleic acid , Gluconic acid, methanesulfonic acid, ethanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, glutamic acid and the like.

The acid addition salt can be prepared by a conventional method. For example, it is possible to dissolve mirabegron in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc., Or may be prepared by distilling the solvent and excess acid under reduced pressure, followed by drying and crystallization in an organic solvent.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving mirabegron in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. In addition, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).

In order to increase the effective efficacy of the active ingredient, it is required to have both a rapid effect for reaching the effective blood concentration within a certain time and a persistence for maintaining the efficacy for a certain period of time.

The controlled release pharmaceutical composition according to the present invention includes a quick-acting polymeric excipient for imparting rapid efficacy.

Particularly, the quick-acting polymer excipient comprises polyvinyl alcohol.

The polyvinyl alcohol may have an average molecular weight of 10 to 2,000,000 g / mol, preferably 100 to 130,000 g / mol, and more preferably 1,000 to 20,000 g / mol.

The polyvinyl alcohol may be characterized in that the 5 wt% aqueous solution has a viscosity of 2 to 10 mPa · s at 25 ° C.

The polyvinyl alcohol is a water-soluble polymer and is included in the release-controlling pharmaceutical composition according to the present invention as a short-acting polymer excipient, thereby improving not only the dissolution rate of mirabegron in water but also the dispersibility and flowability of the controlled- Thereby improving the content uniformity.

Particularly, the polyvinyl alcohol has a small interaction with the main component, so that little or no generation of the flexible substance in the pharmaceutical composition occurs.

In addition, when polyvinyl alcohol is added as a short-acting polymer excipient, the preparations prepared using the final controlled-release pharmaceutical composition show little change in properties, and exhibit improved water stability and content stability.

Accordingly, when polyvinyl alcohol is added as a fast acting polymer excipient, it is possible to omit a separate granulation process, thereby improving the productivity.

In addition, the controlled-release pharmaceutical composition according to the present invention includes a release-controlling agent for imparting the persistence of the drug.

The release control agent may be characterized by containing at least one selected from the group consisting of a water-soluble polymer, a hydrophobic base and a water-insoluble base.

The water-soluble polymer may be at least one selected from the group consisting of polyethylene oxide, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose sodium, hydroxyethylcellulose, and carboxyvinyl polymer.

The water-soluble polymer is a polymer material that forms a hydrogel, and can increase the solubility of the active ingredient in water, and the release rate of the active ingredient can be controlled by controlling the viscosity thereof.

The polyethylene oxide may have an average molecular weight of 10,000 to 15,000,000 g / mol, preferably 500,000 to 10,000,000 g / mol, and more preferably 100,000 to 7,000,000 g / mol.

The hydroxypropyl methylcellulose may have an average molecular weight of 10,000 to 15,000,000 g / mol.

The hydroxypropyl cellulose may have an average molecular weight of 50,000 to 1,250,000 g / mol.

The carboxymethylcellulose sodium may have an average molecular weight of 50,000 to 700,000 g / mol.

The hydroxyethyl cellulose may have an average molecular weight of 50,000 to 1,300,000 g / mol.

The hydrophobic base is at least one selected from the group consisting of C ₈ to C ₂₆ fatty acids, C ₈ to C ₅₀ fatty acid esters, C ₆ to C ₃₀ higher alcohols, hydrogenated vegetable oils, hardened castor oil, and wax .

Preferably, the hydrophobic base may be at least one selected from the group consisting of glyceryl behenate, sorbitan monostearate, stearic acid, glyceryl monostearate and polyoxy glyceride.

In the controlled release pharmaceutical composition according to the present invention, when the hydrophobic base is used as a release-controlling agent, not only the release rate of the active ingredient can be controlled but also the active ingredient can be prevented from being hydrolyzed, Can be prevented.

The polyoxyglyceride may have an average molecular weight of 10 to 30,000 g / mol, preferably 100 to 10,000 g / mol, and more preferably 200 to 4,000 g / mol.

The sorbitan monostearate may have an average molecular weight of 10 to 10,000 g / mol, preferably 100 to 5,000 g / mol, and more preferably 300 to 1,000 g / mol.

The water-insoluble base may be any one selected from the group consisting of polyvinylpyrrolidone-vinyl acetate, polyvinylpyrrolidone-vinyl acetate copolymer and ethylcellulose.

The water-insoluble base may exhibit a solubility of 0.00001 to 0.0001 g / ml in water solvent at any pH.

The water-insoluble base makes it difficult for water to penetrate into the pharmaceutical composition due to the water-insoluble nature, so that the release of the active ingredient slowly takes place.

In addition, it is possible to prevent the active ingredient from being hydrolyzed.

The controlled-release pharmaceutical composition according to the present invention is characterized by further comprising at least one excipient selected from the group consisting of colloidal silicon dioxide, silicon dioxide, microcrystalline cellulose, lactose, corn starch, potassium hydrogen phosphate and pregelatinized starch .

The excipient may be contained in an amount of 0.01 to 100 parts by weight, preferably 0.1 to 50 parts by weight, and more preferably 1 to 30 parts by weight, based on 100 parts by weight of the active ingredient.

Furthermore, the controlled-release pharmaceutical composition according to the present invention may further include at least one lubricant selected from the group consisting of stearate, glyceryl behenate, talc and silicon dioxide.

Examples of the stearate include magnesium stearate, calcium stearate, and zinc stearate, and magnesium stearate is preferably used.

The lubricant may be included in an amount of 0.01 to 100 parts by weight, preferably 0.1 to 50 parts by weight, and more preferably 1 to 30 parts by weight, based on 100 parts by weight of the active ingredient.

The controlled-release pharmaceutical composition according to the present invention may comprise 10 to 1,000 parts by weight of the quick-acting polymer excipient per 100 parts by weight of the active ingredient.

Specifically, 10 to 1,000 parts by weight, preferably 50 to 800 parts by weight, and more preferably 100 to 500 parts by weight of the quick-acting polymer excipient may be included per 100 parts by weight of the active ingredient .

If the content of the fast acting polymeric excipient is less than the above range, the dissolution rate of the active ingredient in water is lowered, the initial release rate is lowered, and the uniformity of the content of the controlled release pharmaceutical composition may be lowered.

In addition, when the content of the short-acting polymer excipient is in excess of the above range, the moisture absorption of the drug may be increased to cause water vulnerability, property change may occur, and the stability of the content of the active ingredient may deteriorate .

The release control agent may be contained in an amount of 1 to 500 parts by weight based on 100 parts by weight of the active ingredient.

Specifically, 1 to 500 parts by weight, preferably 10 to 300 parts by weight, and more preferably 50 to 100 parts by weight of the emission control agent may be contained per 100 parts by weight of the active ingredient .

If the content of the release control agent is less than the above range, the sustainability of the active ingredient may be lowered. If the content is in excess of the above range, the release of the active ingredient may be delayed or the activity of the active ingredient may be inhibited .

The controlled-release pharmaceutical composition according to the present invention can be formulated into various formulations for oral and parenteral administration. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, .

For example, formulations for oral administration can be formulated as tablets, pills, light / soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs, troches and the like.

These formulations may contain a diluent, a lubricant, in addition to the active ingredient. Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose or polyvinylpyrrolidine, and may optionally contain disintegrating agents such as starch, agar, alginic acid or its sodium salt, Boiling mixtures or absorbents, coloring agents, flavoring agents, and sweetening agents.

The parenteral administration of the above pharmaceutical composition may be carried out by injecting subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.

At this time, in order to formulate the composition for parenteral administration, the active ingredient may be mixed with water or a stabilizer or a buffer to prepare a solution or suspension, which may be prepared into an ampoule or vial unit dosage form. The composition may be sterilized or contain an adjuvant such as an antiseptic, a stabilizer, a wetting or emulsifying agent, a salt or buffer for controlling osmotic pressure, and other therapeutically useful substances, and may be mixed, granulated or coated . ≪ / RTI >

Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples. However, the embodiments according to the present invention can be modified into various other forms, and the scope of the present invention should not be construed as being limited to the embodiments described below. Embodiments of the invention are provided to more fully describe the present invention to those skilled in the art.

EXAMPLES 1 to 3 Release-controlled medicinal compositions comprising mirabegron, polyvinyl alcohol and a water-soluble polymer (polyethylene oxide)

The release-controlled medicinal composition was prepared using Mirabegron, polyvinyl alcohol (15,000 g / mol) and polyethylene oxide (1,000,000 g / mol) as a water-soluble polymer as a release controlling agent, and the respective components are shown in Table 1 .

Raw material name Example 1 Example 2 Example 3 Mirabegron 50.00 50.00 50.00 Polyvinyl alcohol 149.20 74.60 223.80 Polyethylene oxide 38.00 38.00 38.00 Colloidal silicon dioxide 5.00 5.00 5.00 Silicon dioxide 5.00 5.00 5.00 Magnesium stearate 3.75 3.75 3.75 Sum 250.95 176.35 325.55

Examples 4 to 8. A controlled release pharmaceutical composition comprising mirabegron, polyvinyl alcohol and a water-soluble polymer

(1,000,000 g / mol), hydroxypropylmethyl cellulose (500,000 g / mol) and hydroxypropyl cellulose (600,000 g / mol) as a release controlling agent, / mol), carboxymethyl cellulose sodium (100,000 g / mol), and hydroxyethyl cellulose (700,000 g / mol) were used to prepare controlled-release pharmaceutical compositions.

Raw material name Example 4 Example 5 Example 6 Example 7 Example 8 Mirabegron 50.00 50.00 50.00 50.00 50.00 Polyvinyl alcohol 149.20 149.20 149.20 149.20 149.20 Polyethylene oxide 38.00 - - - - Hydroxypropylmethylcellulose - 38.00 - - - Hydroxypropylcellulose - - 38.00 - - Carboxymethylcellulose sodium - - - 38.00 - Hydroxyethylcellulose - - - - 38.00 Colloidal silicon dioxide 5.00 5.00 5.00 5.00 5.00 Silicon dioxide 5.00 5.00 5.00 5.00 5.00 Magnesium stearate 3.75 3.75 3.75 3.75 3.75 Sum 250.95 250.95 250.95 250.95 250.95

Examples 9 to 13. A controlled release pharmaceutical composition comprising mirabegron, polyvinyl alcohol and a hydrophobic base

(300 g / mol), sorbitan monostearate (700 g / mol), stearic acid (284.47 g / mol), polyvinyl alcohol (15,000 g / mol) and a hydrophobic base, such as glyceryl behenate (358.6 g / mol) and polyoxyglyceride (1,500 g / mol) were used to prepare controlled-release pharmaceutical compositions.

Raw material name Example 9 Example 10 Example 11 Example 12 Example 13 Mirabegron 50.00 50.00 50.00 50.00 50.00 Polyvinyl alcohol 149.20 149.20 149.20 149.20 149.20 Glyceryl behenate 38.00 - - - - Sorbitan monostearate - 38.00 - - - Stearic acid - - 38.00 - - Glyceryl monostearate - - - 38.00 - Polyoxyglyceride - - - - 38.00 Colloidal silicon dioxide 5.00 5.00 5.00 5.00 5.00 Silicon dioxide 5.00 5.00 5.00 5.00 5.00 Magnesium stearate 3.75 3.75 3.75 3.75 3.75 Sum 250.95 250.95 250.95 250.95 250.95

Examples 14 to 16. A controlled release pharmaceutical composition comprising mirabegron, polyvinyl alcohol and a water-insoluble base

The controlled-release pharmaceutical composition was prepared using a water-insoluble base material such as mirabegron, polyvinyl alcohol, and a release-controlling agent, and the respective components are shown in Table 4.

Raw material name Example 14 Example 15 Example 16 Mirabegron 50.00 50.00 50.00 Polyvinyl alcohol 149.20 149.20 149.20 Polyvinylpyrrolidone-vinyl acetate 38.00 - - Polyvinylpyrrolidone-vinyl acetate copolymer - 38.00 - Ethyl cellulose - - 38.00 Colloidal silicon dioxide 5.00 5.00 5.00 Silicon dioxide 5.00 5.00 5.00 Magnesium stearate 3.75 3.75 3.75 Sum 250.95 250.95 250.95

COMPARATIVE EXAMPLES 1 to 4 Release-controlled medicinal compositions comprising mirabegron, a short-acting polymer excipient other than polyvinyl alcohol, and a water-soluble polymer

(182.17 g / mol), hydroxypropylmethylcellulose (500,000 g / mol), hydroxypropylcellulose (600,000 g / mol) and polyethylene glycol (4,500 g / mol) instead of polyvinyl alcohol as a fast- mol) were respectively used to prepare a pharmaceutical composition for controlled release of Mirabegron, and the respective components are shown in Table 5.

Raw material name Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Mirabegron 50.00 50.00 50.00 50.00 Polyethylene oxide 38.00 38.00 38.00 38.00 D-mannitol 149.20 - - - Hydroxypropylmethylcellulose - 149.20 - - Hydroxypropylcellulose - - 149.20 - Polyethylene glycol - - - 149.20 Colloidal silicon dioxide 5.00 5.00 5.00 5.00 Silicon dioxide 5.00 5.00 5.00 5.00 Magnesium stearate 3.75 3.75 3.75 3.75 Sum 250.95 250.95 250.95 250.95

Experimental Example 1. Evaluation of the solubility of mirabegron

(1) Experimental method

The solubility of mirabegron in water and different pH conditions was confirmed.

(2) Experimental results

The results of the above experiment are shown in Table 6.

As shown, there was no significant difference in the solubility by pH, but it was confirmed that the solubility in water was remarkably low.

Solubility Water practically insoluble in water 0.1N HCL 203 ug / mL Citrate buffer pH 3.0 199 ug / mL Acetate buffer pH 4.5 195 ug / mL Phosphate buffer pH 6.8 199 ug / mL Phosphate buffer pH 7.5 194 ug / mL

Experimental Example 2. Estimation of dissolution rate of pharmaceutical composition containing controlled release of mirabegron

(1) Experimental method

Using the controlled-release pharmaceutical compositions prepared in Examples 1 to 16 and Comparative Examples 1 to 4, the test solution and the standard solution eluted at 200 rpm in the second method of the Korean Pharmacopoeia Method were dissolved in water to a concentration of about 0.01 mg / mL The dissolution rate was evaluated by measuring the absorbance at 247 nm according to the method of measuring the absorbance of the absorbance spectra.

(2) Experimental results

The results of the above experiment are shown in Table 7 and Fig.

As shown, it was confirmed that the dissolution rates of Examples 1 to 16 in which polyvinyl alcohol was added were higher than those of Comparative Examples 1 to 4 in which polyvinyl alcohol was not contained.

Through this, it was found that the solubilization of polyvinyl alcohol greatly improved the solubility of mirabegron in water.

Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 90 minutes 26.6 22.8 23.9 24.1 24.1 26.4 25.8 27.1 150 minutes 49.2 42.1 45.1 40.9 42.9 44.3 46.8 43.9 270 minutes 91.9 81.6 88.3 80.6 89.2 83.8 89.1 81.9 Example 9 Example 10 Example 11 Example 12 Example 13 Example 14 Example 15 Example 16 90 minutes 26.2 27.9 25.4 24.8 25.8 26.2 27.1 25.8 150 minutes 48.2 50.2 45.9 44.3 48.2 46.8 49.2 44.7 270 minutes 93.9 92.3 89.1 85.4 90.4 84.2 89.1 85.4 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 90 minutes 11.2 10.9 12.8 24.1 150 minutes 22.1 21.3 26.1 46.2 270 minutes 50.1 43.9 60.2 89.2

Experimental Example 3. Evaluation of uniformity of contents of controlled-release pharmaceutical composition containing mirabegron

(1) Experimental method

Each of the above Examples 1 to 5 and Comparative Examples 1 to 4 was mixed with a 20-mesh sieve. After 5 minutes of simple mixing, the test solution and standard solution were dissolved in 50% methanol to a concentration of 0.01 mg / mL. And the content uniformity was evaluated.

(2) Experimental results

The results of the above experiment are shown in Table 8.

As shown, it was confirmed that Examples 1 to 5 in which polyvinyl alcohol was added exhibited better dispersing ability and flowability than Comparative Examples 1 to 4 in which polyvinyl alcohol was not contained.

Therefore, it was found that when the polyvinyl alcohol is added, the granulation process can be omitted and the productivity can be improved.

Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Prize 100.5 101.5 101.4 98.5 100.8 100.3 99.2 medium 100.7 98.5 99.6 99.8 99.1 98.2 98.3 Ha 100.1 98.1 103.0 101.3 98.7 98.5 101.4 Average 100.4 99.4 101.3 99.9 99.5 99.0 99.6 Standard Deviation 0.3 1.9 1.7 1.4 1.1 1.1 1.6 Example 8 Example 9 Example 10 Example 11 Example 12 Example 13 Example 14 Prize 102.0 99.2 100.8 97.9 99.2 100.3 101.3 medium 101.8 98.1 100.1 101.4 101.3 99.1 99.2 Ha 99.2 101.3 98.3 99.3 100.8 101.4 99.1 Average 101.0 99.5 99.7 99.5 100.4 100.3 99.9 Standard Deviation 1.6 1.6 1.3 1.8 1.1 1.2 1.2 Example 15 Example 16 Prize 99.1 98.7 medium 102.1 101.3 Ha 101.8 100.8 Average 101.0 100.3 Standard Deviation 1.7 1.4 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Prize 90.6 100.1 103.5 109.0 medium 109.5 92.6 93.4 99.1 Ha 92.8 107.0 106.9 92.8 Average 97.6 99.9 101.3 100.3 Standard Deviation 10.3 7.2 7.0 8.2

Experimental Example 4: Flexible test of pharmaceutical composition containing controlled release of mirabegron

(1) Experimental method

In order to evaluate the interaction between the Examples 1 to 16 and the Comparative Examples 1 to 4 with the main component according to the fast acting polymer excipient under the storage conditions for 2 months under accelerated conditions (45 ° C, 75% relative humidity) 1.0 mg / mL) and standard solution (0.001 mg / mL) were evaluated by HPLC on a C18 column at a wavelength of 215 nm.

(2) Experimental results

The results of the above experiment are shown in Table 9.

As shown, in comparison with Examples 1 to 16 in which polyvinyl alcohol was used as the fast acting polymer excipient, D-mannitol was used instead of polyvinyl alcohol. In Comparative Examples 1 to 4 using hydroxypropylmethylcellulose, hydroxypropylcellulose and polyethylene glycol, storage stability under the accelerated conditions of 0.5% or less was not satisfied when the product was stored for 2 months.

In addition, it was confirmed that Examples 1 to 16 were very small in interaction with the main component and thus stable to the generation of a flexible substance.

Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Flexible material
(Impurity C) 0.0% 0.2% 0.3% 0.1% 0.3% 0.2% 0.3% Total flexible material 0.0% 0.2% 0.5% 0.4% 0.5% 0.5% 0.4% Example 8 Example 9 Example 10 Example 11 Example 12 Example 13 Example 14 Flexible material
(Impurity C) 0.2% 0.1% 0.3% 0.2% 0.4% 0.2% 0.2% Total flexible material 0.3% 0.4% 0.5% 0.5% 0.5% 0.3% 0.4% Example 15 Example 16 Flexible material
(Impurity C) 0.2% 0.3% Total flexible material 0.4% 0.5% Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Flexible material
(Impurity C) 3.4% 2.8% 3.1% 3.4% Total flexible material 5.5% 4.1% 5.1% 5.7%

Impurity C means a compound represented by Chemical Formula 1, and its chemical name is (1R) -2 - {[2- (4-aminophenyl) ethyl] amino} -1-phenylethanol 1R) -2 - {[2- (4-aminophenyl) ethyl] amino} -1-phenylethanol).

EXPERIMENTAL EXAMPLE 5. Observation of change in property of a medical preparation formulated with a controlled-release pharmaceutical composition containing mirabegron

(1) Experimental method

In order to observe the change of properties according to the fast acting polymer excipient, the changes of the properties of the pressed preparations prepared in Examples 1, 3, 5 and Comparative Examples 1 and 4 were observed.

(2) Experimental results

The results of the above experiment are shown in Fig.

As shown, in Examples 1, 3, and 5 using polyvinyl alcohol as a short-acting polymer excipient, there was no color change or little color change, but in Comparative Examples 1 and 4 in which polyvinyl alcohol was not used, I could confirm.

Particularly, in the case of Example 1, it was observed that there was no color change at all.

Experimental Example 6. Assessment of water stability of a preparation made of pharmaceutical composition containing controlled release of mirabegron

(1) Experimental method

10 tablets of the preparations prepared using the above Examples 1 to 16 and Comparative Examples 1 to 4 were stored for 2 months under accelerated conditions (45 ° C, 75% relative humidity), and the weights before and after storage were measured. Respectively.

(2) Experimental results

The results of the above experiment are shown in Table 10.

Compared with Examples 1 to 16 in which polyvinyl alcohol was used as the fast acting polymeric excipient, as shown in Comparative Examples 1 to 4 in which D-mannitol, hydroxypropylmethylcellulose, hydroxypropylcellulose and polyethylene glycol were used in place of polyvinyl alcohol Showed that the rate of increase / decrease of the weight difference was remarkably small.

As a result, it was found that the stability of tablets vulnerable to moisture was improved in Examples 1 to 16.

(mg) Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Before storage 2573.8 2574.3 2581.1 2573.2 2570.5 2449.2 2237.8 After storage 2576.8 2585.6 2589.4 2584.3 2586.7 2471.3 2263.7 Weight difference 3.0 11.3 8.3 11.1 16.2 22.1 25.9 Rate of increase / decrease (%) +0.1 +0.4 +0.3 +0.4 +0.6 +0.9 +1.2 Example 8 Example 9 Example 10 Example 11 Example 12 Example 13 Example 14 Before storage 2415.6 2410.8 2224.8 2481.3 2440.2 2462.3 2556.4 After storage 2444.1 2443.9 2234.1 2500.3 2476.6 2483.1 2574.3 Weight difference 28.5 33.1 9.3 19 36.4 20.8 17.9 Rate of increase / decrease (%) +1.2 +1.4 +0.4 +0.8 +1.5 +0.8 +0.7 Example 15 Example 16 Before storage 2537.9 2427.9 After storage 2569.1 2458.1 Weight difference 31.2 30.2 Rate of increase / decrease (%) +1.2 +1.2 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Before storage 2574.6 2574.0 2576.1 2549.6 After storage 2690.2 2683.2 2696.6 2673.2 Weight difference 115.6 109.2 120.5 123.6 Rate of increase / decrease (%) +4.5 +4.2 +4.7 +4.8

EXPERIMENTAL EXAMPLE 7. Evaluation of the content stability of a preparation made of pharmaceutical composition containing controlled release of mirabegron

(1) Experimental method

The contents of the samples were measured before and after storage under the accelerated conditions (45 ° C, 75% relative humidity) for 2 months, and the stability of the samples was evaluated by using the samples of Examples 1 to 16 and Comparative Examples 1 to 4.

(2) Experimental results

The results of the above experiment are shown in Table 11.

As shown, in Examples 1 to 16 using polyvinyl alcohol as a fast acting polymer excipient, Comparative Examples 1 to 4 using D-mannitol, hydroxypropylmethylcellulose, hydroxypropylcellulose and polyethylene glycol instead of polyvinyl alcohol and It was confirmed that the difference in content was remarkably small.

As a result, it was found that the content stability of Examples 1 to 16 was remarkably excellent.

(%) Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Before storage 100.8 100.2 102.0 101.9 100.2 100.8 101.3 After storage 100.6 99.7 100.9 100.6 99.7 99.2 100.4 Content difference -0.2 -0.5 -1.1 -1.3 -0.5 -1.6 -0.9 Example 8 Example 9 Example 10 Example 11 Example 12 Example 13 Example 14 Before storage 100.8 100.6 100.7 101.3 100.9 100.1 100.8 After storage 100.1 99.7 100.4 100.9 100.2 99.3 100.0 Content difference -0.7 -0.9 -0.3 -0.4 -0.7 -0.8 -0.8 Example 15 Example 16 Before storage 101.2 100.6 After storage 100.2 100.2 Content difference -1.0 -0.4 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Before storage 101.7 102.0 99.8 101.6 After storage 97.2 96.8 95.7 96.1 Content difference -4.5 -5.2 -4.1 -5.5

Claims (9)

An effective ingredient, a quick-acting polymer excipient and a release-controlling agent containing mirabegron or a pharmaceutically acceptable salt thereof,
Wherein the quick-acting polymeric excipient comprises polyvinyl alcohol,
Wherein the release control agent comprises any one or more selected from the group consisting of a water-soluble polymer, a hydrophobic base, and a water-insoluble base.
The method according to claim 1,
Wherein the water-soluble polymer is at least one selected from the group consisting of polyethylene oxide, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose sodium, hydroxyethylcellulose, and carboxyvinyl polymer.
The method according to claim 1,
The hydrophobic base is at least one selected from the group consisting of C ₈ to C ₂₆ fatty acids, C ₈ to C ₅₀ fatty acid esters, C ₆ to C ₃₀ higher alcohols, hydrogenated vegetable oils, hardened castor oil, and wax Or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
Wherein the water-insoluble base is at least one selected from the group consisting of polyvinylpyrrolidone-vinyl acetate, polyvinylpyrrolidone-vinyl acetate copolymer and ethylcellulose.
The method according to claim 1,
Wherein the composition further comprises one or more excipients selected from the group consisting of colloidal silicon dioxide, silicon dioxide, microcrystalline cellulose, lactose, corn starch, potassium hydrogen phosphate and pregelatinized starch.
The method according to claim 1,
Wherein the composition further comprises at least one lubricant selected from the group consisting of stearates, glyceryl behenate, talc, and silicon dioxide.
The method according to claim 1,
Wherein the fast acting polymeric excipient is contained in an amount of 10 to 1,000 parts by weight based on 100 parts by weight of the active ingredient.
The method according to claim 1,
Wherein the release control agent is contained in an amount of 1 to 500 parts by weight based on 100 parts by weight of the active ingredient.
The method according to claim 1,
Wherein the polyvinyl alcohol has a 5 wt% aqueous solution having a viscosity at 25 캜 of 2 to 10 mPa s.

Images