KR102018495B1 - Sustained-release bilayer tablets for the treatment of overactive bladder And method for manufacturing the same - Google Patents

Abstract

The present invention provides: a sustained-release bilayer tablet composed of a corrosive first layer containing a mirabegron and an emission control mechanism and a swelling second layer containing fesoterodine and a water-soluble gelling agent; and a method for manufacturing the same. According to the present invention, the sustained-release bilayer tablet according to the present invention can increase medication compliance by increasing convenience of taking by allowing the mirabegron and fesoterodine which have a different dissolution pattern to have a same dissolution pattern as an existing single agent in one tablet.

Description

Sustained-release bilayer tablets for the treatment of overactive bladder And method for manufacturing the same

The present invention relates to a sustained release bilayer tablet for the treatment of overactive bladder and a method of manufacturing the same, more specifically an erosive first layer comprising a mirabegron and a release control mechanism; And a sustained release bilayer tablet for the treatment of an overactive bladder composed of a swellable second layer comprising pesoterodine and a water-soluble gelling agent, and a method for preparing the same.

Irritable bladder is a disease that causes symptoms such as urinary frequency and nocturnal urination. This tends to increase with age, and 3 out of 10 patients with irritable bladder are frequently observed.

In order to ameliorate the symptoms, substances that act as beta-3 adrenergic agonists and muscarinic receptor antagonists have been used. I'm getting prescription.

Currently, the two types of drugs are prescribed as above, and each of them needs to be taken as a single agent, and when prepared as a single tablet, the medication compliance of the patient may be increased and further, the drug treatment may be improved.

However, when two types of drugs prescribed as a single drug are not well suited, it is difficult to make one tablet. In addition, Mirabegron has a characteristic of maximizing therapeutic effect when reaching 100% drug dissolution at 8 hours and pesoterodine at 20 hours. That is, the two drugs have different optimal drug release rates. As these two drugs have different sustained release elution patterns, this is also a difficult factor when making one tablet.

Accordingly, the present inventors have made intensive research efforts to overcome the problems of the prior art, the first layer of erosion comprising a mirabegron and an emission control mechanism; And, in the case of a sustained release bilayer tablet composed of a swellable second layer containing pesoterodine and a water-soluble gelling agent, Mirabegron and pesoterodine having different elution patterns have the same elution pattern as the conventional single agent. It was confirmed that it can increase the compliance with the medication by increasing the convenience of taking, and completed the present invention.

KR 10-2017-0088783 A

The present invention comprises Mirabegron, which has a dissolution pattern different from Mirabegron and Pesoterodine, in one tablet, having the same dissolution pattern as a conventional single agent, to increase the drug compliance according to the increase in convenience of taking as an active ingredient. Erosive first layer; And a sustained release bilayer tablet composed of a swellable second layer comprising pesoterodine as an active ingredient.

Another object of the present invention is to provide a production method for producing a sustained release bilayer tablet according to the present invention.

According to one aspect of the present invention, the present invention provides a corrosive first layer comprising mirabegron as an active ingredient; And a swellable second layer comprising pesoterodine as an active ingredient.

Conventional medication compliance is low because both conventional tablets containing mirabegron and pesoterodine as a drug for treating an overactive bladder have to be taken. In order to improve medication compliance, attempts have been made to include the two drugs in one tablet, but since the dissolution patterns of the two drugs are different, it is difficult to make one tablet.

Accordingly, the present inventors, in order to prepare a mirabegron and pesoterodine having a different dissolution pattern into one tablet having the same dissolution pattern as a conventional single agent, the layer containing the mirabegron is composed of erosion and pesoterodine The layer containing is to solve the above problems by producing one sustained-release tablet consisting of swelling.

In the sustained release bilayer tablet according to the present invention, the release controlling agent may also include any release controlling agent used for sustained release of the drug, preferably hydroxypropyl cellulose, low substituted-hydroxypropyl cellulose, basic It may include one or more selected from the group consisting of butylated methacrylate copolymer, chitosan, and propylene glycol alginate, more preferably hydroxypropyl cellulose or low-substituted hydroxypropyl cellulose alone, or It is characterized by including a mixture.

In the sustained release bilayer tablet according to the present invention, the water-soluble gelling agent conventionally swells rapidly upon contact with an aqueous medium such as gastric juice to lower the density of the preparation and control any rapid rapid release of the drug. Drawing, preferably, xanthan gum, alginic acid, calcium alginate, carbomer, gelatin, glyceryl bicarbonate, glyceryl monorate, polyethylene oxide, ethyl cellulose, polyvinylacetate, cellulose acetate, hydroxymethyl cellulose, It may include one or more selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl methyl cellulose, propylene glycol, polyethylene glycol and carboxymethyl cellulose sodium, more preferably characterized by comprising hydroxypropyl methyl cellulose do.

The hydroxypropylmethylcellulose swells upon contact with water to form a kind of gel layer, through which the formulation is continuously suspended and swelled so that the formulation remains in the gastrointestinal tract for a long time. In addition, by delaying the release of the pharmacologically active ingredient, the bioavailability can be increased by allowing the pharmacologically active ingredient to specifically retain the absorption site or the site of action for a long time.

Therefore, pesoterodine, which can maximize the therapeutic effect only after releasing the drug for about 20 hours, is composed of a swellable second layer using a water-soluble gelling agent, so that the therapeutic effect can be maximized only when the drug is released for about 8 hours. Even if the erosive first layer, including the miravegron, is released for eight hours, the second layer can release the drug longer by swelling.

In the sustained-release bilayer tablet according to the present invention, the miravegron content of the erosive first layer may be determined in consideration of the daily dose and the solubility with the solvent, in which the pharmacological effect is sufficiently exerted and no adverse effects occur. It is characterized in that it comprises 10 to 100mg. If the content of the Mirabegron is less than 10mg, the concentration of the Mirabegron is not sufficient to exhibit sufficient pharmacological effect. If the content of the Mirabegron exceeds 100mg, the concentration of Mirabegron is high, so that its compatibility with pesoterodine is lowered, and thus the sustained-release double-layer tablet is used. It is not desirable to prepare.

In the sustained release bilayer tablet according to the present invention, the release control mechanism content of the first layer of erosion may be determined in consideration of the release pattern of the drug and the compatibility with the combination of pesoterodine, and preferably 150 to 200 mg. Characterized in that. If the content of the release control mechanism is less than 150mg, it is difficult to control the release pattern of the drug in a sustained release form, and if it exceeds 200mg, it is not preferable to prepare a sustained release bilayer tablet due to low compatibility with pesoterodine.

In the sustained-release bilayer tablet according to the present invention, the pesoterodine content of the swellable second layer may be determined in consideration of the daily dose and the solubility with the solvent, in which the pharmacological effect is sufficiently exerted and no adverse effects occur. Preferably it is characterized in that it comprises 2 to 10mg. If the content of pesoterodine is less than 2 mg, the concentration of pesoterodine may not be sufficient to exert sufficient pharmacological effect. If the content of the pesoterodine is greater than 10 mg , the concentration of pesoterodine is high, and therefore, the compatibility with Mirabegron is low, and thus the sustained-release double-layer tablet is used. It is not desirable to prepare.

In the sustained release bilayer tablet according to the present invention, the water-soluble gelling agent content of the swellable second layer may be determined in consideration of the degree of gelation and swelling and the residence time, and preferably 50 to 150 mg. do. If the content of the water-soluble gelling agent is less than 50mg, it is difficult to control the release pattern of the drug to sustained release. If the content of the water-soluble gelling agent exceeds 150mg, it is not preferable to prepare one sustained-release bilayer tablet because of low compatibility with Mirabegron.

In the sustained release bilayer tablet according to the present invention, the erosive first layer further comprises at least one additive selected from the group consisting of magnesium stearate, ferric oxide red, polyethylene oxide and poloxamer.

In the sustained release bilayer tablet according to the invention, the swellable second layer further comprises at least one additive selected from the group consisting of erythritol, rudipress, compritol and talc.

In the sustained release bilayer tablet according to the present invention, the sustained release bilayer tablet has an average diameter of 10 to 15 mm.

According to another aspect of the invention, the invention

A first step of mixing and tableting granules, powder or granulated powder of the first layer of erosion; And

A second step of tableting by adding granules, powder or granulated powder of the swellable second layer on the tablet tableted in the first step; It provides a method for producing a sustained release bilayer tablet consisting of.

In the method for producing a sustained release bilayer tablet of the present invention, the first step is characterized in that the tableting at a pressure of 0.3 to 0.8 ton / m ² .

In the method for producing a sustained release bilayer tablet of the present invention, the second step is characterized in that the tableting at a pressure of 0.9 to 1.5 ton / m ² .

As described above, the sustained release bilayer tablet according to the present invention composed of an erosive first layer containing mirabegron and a swellable second layer containing pesoterodine has a different pattern of miravegron and pesote having different elution patterns. Rodin has the same dissolution pattern as the dissolution pattern of a single drug even in one tablet, thereby increasing the medication compliance according to the convenience of taking.

1 is a view showing the results of the experiment according to the present invention Experimental Example 1.
2 is a view showing the results of the experiment according to the present invention.
Figure 3 is a view showing the results of the experiment according to the present invention Experimental Example 3.
4 and 5 are diagrams showing the experimental results according to the experimental example 4 of the present invention.
6 and 7 are diagrams showing the experimental results according to the experimental example 4 of the present invention.
8 is a view showing the appearance according to the elution time of the sustained release bilayer tablet according to the present invention.

Hereinafter, the present invention will be described in more detail with reference to Examples. Since these examples are only for illustrating the present invention, the scope of the present invention is not to be construed as being limited by these examples.

Example 1 Preparation of Sustained-Release Tablets Containing Mirabegron Only

50 mg of Mirabegron, 19 mg of polyethylene oxide (WSR®-301), 48 mg of poloxamer 188 formulated as No. 30, and 178 mg of hydroxypropylcellulose (Klucel® JF Pharm) were added to the mortar and mixed using pestle. . Then 5 mg of magnesium stearet was added to prepare a mixture for use in the mirabegron single agent. The dose is a dose per tablet, and was prepared by precisely weighing an amount corresponding to 50 tablets for convenience of the manufacturing process.

The tableting was tableted at 1ton / m ² using an 11mm rectangular die and a punch to prepare a sustained-release tablet.

Example 2: Preparation of Sustained-Release Tablets Containing Mirabegron

Miravegron 50 mg, Polyethylene oxide (WSR®-301) 19 mg, 48 mg poloxamer 188, 28 mg hydroxypropyl cellulose (Klucel® JF Pharm), 150 mg low-substituted hydroxypropyl cellulose Was added to the mortar and mixed using a pestle. Then 5 mg of magnesium stearet was added to prepare a mixture for use in the mirabegron single agent. The dose is a dose per tablet, and was prepared by precisely weighing an amount corresponding to 50 tablets for convenience of the manufacturing process.

The tableting was tableted at 1 ton / m 2 using an 11 mm rectangular die and punch to prepare a sustained-release tablet.

Example 3: Preparation of Sustained-Release Tablets Containing Mirabegron

Miravegron 50 mg, Polyethylene oxide (WSR®-301) 19 mg, 48 mg of poloxamer 188 formulated in No. 30, hydroxypropyl cellulose (Klucel® JF Pharm) 58 mg, low-substituted hydroxypropyl cellulose 120 mg Was added to the mortar and mixed using a pestle. Then 5 mg of magnesium stearet was added to prepare a mixture for use in the mirabegron single agent. The dose is a dose per tablet, and was prepared by precisely weighing an amount corresponding to 50 tablets for convenience of the manufacturing process.

The tableting was compressed to 1 ton / m ² using an 11 mm rectangular die and a punch to prepare a sustained-release tablet.

Example 4: Preparation of Sustained-Release Tablets Containing Mirabegron

50 mg of Mirabegron, 19 mg of polyethylene oxide (WSR®-301), 48 mg of poloxamer 188 established in No. 30, and 178 mg of low substituted-hydroxypropylcellulose were added to the mortar and mixed using a pestle. Then 5 mg of magnesium stearet was added to prepare a mixture for use in the mirabegron single agent. The dose is a dose per tablet, and was prepared by precisely weighing an amount corresponding to 50 tablets for convenience of the manufacturing process.

The tableting was compressed to 1 ton / m ² using an 11 mm rectangular die and a punch to prepare a sustained-release tablet.

Example 5 Preparation of Sustained-Release Tablets Containing Mirabegron and Pesoterodine

1) Miravegron West

50 mg of Mirabegron, 19 mg of polyethylene oxide (WSR®-301), 48 mg of poloxamer 188 formulated as No. 30, and 178 mg of hydroxypropylcellulose (Klucel® JF Pharm) were added to the mortar and mixed using pestle. . Thereafter, 3 mg of ferric oxide red and 5 mg of magnesium stearet were added to prepare a mixture to be used for the mirabegron layer. The dose is a dose per tablet, and was prepared by precisely weighing an amount corresponding to 50 tablets for convenience of the manufacturing process.

2) Pesoterodine Western Layer

4 mg of pesoterodine and 36 mg of erythritol were identified as No. 45 and mixed. After catching the wet granules while adding the appropriate amount of purified water, it was settled in No. 18 sieve, and dried for 3 hours at 60 ℃ dry oven conditions. The dried granules were sized into No. 30 and used as a premix of the muscarinic receptor antagonist layer. Premix, ludipress, hydroxypropylmethylcellulose, and compritol were respectively placed in No. 30 and mixed.

The talc established as a No. 60 sieve in the mixture was then mixed to prepare granules to be used in the pesoterodine layer. The dose is a dose per tablet, and was prepared by precisely weighing an amount corresponding to 50 tablets for convenience of the manufacturing process.

3) tableting

It was compressed using a 14 mm rectangular die and punch. After filling the Mirabegron layer mixture, it was compressed to 0.5 ton / m ² , and added to the pesoterodine layer granules, and then to 1 ton / m ² to prepare a sustained-release tablet.

Example 6: Preparation of Sustained-Release Tablets Containing Mirabegron and Pesoterodine

1) Miravegron West

50 mg of Mirabegron, 19 mg of polyethylene oxide (WSR®-301), 48 mg of poloxamer 188 established in No. 30, and 178 mg of low substituted-hydroxypropylcellulose were added to the mortar and mixed using a pestle. Then, 3 mg of ferric oxide red and 5 mg of magnesium stearet were added to prepare a mixture to be used for the mirabegron layer. The dose is a dose per tablet, and was prepared by precisely weighing an amount corresponding to 50 tablets for convenience of the manufacturing process.

2) Pesoterodine Western Layer

4 mg of pesoterodine and 36 mg of erythritol were identified as No. 45 and mixed. After catching the wet granules while adding the appropriate amount of purified water, it was settled in No. 18 sieve and dried for 3 hours at 60 ℃ dry oven conditions. The dried granules were sized into No. 30 and used as a premix of the muscarinic receptor antagonist layer. Premix, ludipress, hydroxypropylmethylcellulose, and compritol were respectively placed in No. 30 and mixed.

The talc established as a No. 60 sieve in the mixture was then mixed to prepare granules to be used in the pesoterodine layer. The dose is a dose per tablet, and was prepared by precisely weighing an amount corresponding to 50 tablets for convenience of the manufacturing process.

3) tableting

It was compressed using a 14 mm rectangular die and punch. After filling the Mirabegron layer mixture, it was compressed to 0.5 ton / m ² , and added to the pesoterodine layer granules, and then to 1 ton / m ² to prepare a sustained-release tablet.

Example 7: Preparation of Sustained-Release Tablets Containing Mirabegron and Pesoterodine

1) Miravegron West

Miravegron 50 mg, Polyethylene oxide (WSR®-301) 19 mg, 48 mg poloxamer 188 , 28 mg hydroxypropyl cellulose (Klucel® JF Pharm), 150 mg low-substituted hydroxypropyl cellulose Was added to the mortar and mixed using a pestle. Thereafter, 3 mg of ferric oxide red and 5 mg of magnesium stearet were added to prepare a mixture to be used for the mirabegron layer. The dose is a dose per tablet, and was prepared by precisely weighing an amount corresponding to 50 tablets for convenience of the manufacturing process.

2) Pesoterodine Western Layer

4 mg of pesoterodine and 36 mg of erythritol were identified as No. 45 and mixed. After catching the wet granules while adding the appropriate amount of purified water, it was settled in No. 18 sieve and dried for 3 hours at 60 ℃ dry oven conditions. The dried granules were sized into No. 30 and used as a premix of the muscarinic receptor antagonist layer. Premix, ludipress, hydroxypropylmethylcellulose, and compritol were respectively placed in No. 30 and mixed.

The talc established as a No. 60 sieve in the mixture was then mixed to prepare granules to be used in the pesoterodine layer. The dose is a dose per tablet, and was prepared by precisely weighing an amount corresponding to 50 tablets for convenience of the manufacturing process.

3) tableting

It was compressed using a 14 mm rectangular die and punch. After filling the Mirabegron layer mixture was compressed to 0.5 ton / m ² and added pesoterodine layer granules on it to a tablet to 1 ton / m ² to prepare a bilayer sustained-release tablet.

Comparative Example 1: sustained-release tablet containing only Mirabegron

As a comparative example, a commercial Mirabegron-containing sustained-release tablet (Betamiga®) was purchased and used for the experiment.

Comparative Example 2: Sustained-release tablet containing only pesoterodine

As a comparative example, a commercially available pesoterodine-containing sustained-release tablet (Toviez®) was purchased and used for the experiment.

The compositions for Examples 1-7 are listed in Tables 1 and 2 below.

Example 1 Example 2 Example 3 Example 4 Mirabegron (mg) 50 50 50 50 Polyethylene Oxide (WSR ^® -301) (mg) 19 19 19 19 Poloxamer ^® 188 (# 30 sieve) (mg) 48 48 48 48 Hydroxypropylcellulose (klucel ^® JF Pharm) (mg) 178 28 58 - Low Substituted-Hydroxypropylcellulose (mg) - 150 120 178 Magnesium Stearate (mg) 5 5 5 5 Mirabegron layer (mg) 300 300 300 300

Example 5 Example 6 Example 7 Mirabegron (mg) 50 50 50 Polyethylene Oxide (WSR ^® -301) (mg) 19 19 19 Poloxamer ^® 188 (# 30 sieve) (mg) 48 48 48 Hydroxypropylcellulose (klucel ^® JF Pharm) (mg) 178 - 28 Low Substituted-Hydroxypropylcellulose (mg) - 178 150 Ferric Oxide Red (mg) 3 3 3 Magnesium Stearate (mg) 5 5 5 Mirabegron layer (mg) 303 303 303 Mix Pre mix Pesoterodine (mg) 4 4 4 Erythritol (mg) 36 36 36 Purified water (mg) q.s q.s q.s Rudipress (mg) 120 120 120 Hydroxypropylmethylcellulose-100.0K cp (mg) 70 70 70 Hydroxypropylmethylcellulose-4.0K cp (mg) 60 60 60 Compritol (mg) 10 10 10 Talc (mg) 8.5 8.5 8.5 Pesoterodine layer (mg) 308.5 308.5 308.5

Experimental Example 1: Evaluation of Mirabegron Formulation Compatibility with Pesoterodine

Pesoterinine 10 mg and Mirabegron 10 mg were established as No. 45, and then stored at 15 ml conical C and 83% relative humidity for 10 days. The mixture before storage, the mixture after 3 days of storage, the mixture after 5 days of storage, and the mixture after 10 days of storage were taken as samples, and each sample was confirmed by three pieces. Mirabegron 10 mg was compared in the same manner as above, and the results are shown in FIG. 1.

As a result, as can be seen in Figure 1, the amount of drug does not change even 10 days of storage of the Mirabegron unmixed with pesoterodine, but in a mixture of Mirabegron and pesoterodine 1: 1 storage 3 On day 1, the amount of drug was reduced by about 50%, and on day 10 it was confirmed that the amount of drug was reduced by 75% or more.

These results show that it is necessary to establish the optimal conditions for mixing Mirabegron and Pesoterodine into one tablet.

Test Example 2: Evaluation of Form and Hardness

The tablets tableted in Examples 5 to 7 were observed for appearance observation, size measurement, and hardness, and the results are shown in FIGS. 2 and 3.

Example 6 Example 7 Example 8 Tablet size
(Rectangle / height / width) (mm) 14.0 / 7.1 / 7.0 14.0 / 7.0 / 6.6 14.0 / 7.0 / 6.7 Hardness ± standard deviation (N) 162.17 ± 3.75 148.50 ± 11.03 138.33 ± 8.95

As a result, as can be seen in Figure 2 and Table 3, the beta-3 adrenergic receptor agonist layer in Example 6 and Example 7 containing low-substituted hydroxypropyl cellulose is lighter than the hydroxypropyl cellulose Example 5 Observed in color, it was confirmed that the hardness is slightly weakened, but has sufficient hardness as a tablet.

Experimental Example 3: Dissolution test of the Mirabegron sustained release single agent of Examples 1 to 4

1) Preparation of Mirabegron

Specimens were prepared by taking three equivalent amounts of Mirabegron 50 mg with respect to the Mirabegron mixture of Examples 1 to 4. Using eluent 900 mL of pH 6.8 buffer, three specimens from each solution were added and a sinker was added to the elution test method 2 at 37 rpm and 100 rpm. After 1 hour, 3 hours, 5 hours, 7 hours, and 8.5 hours, 5 mL of the eluate was taken out, and the filtrate filtered with a membrane filter having 0.45 μm pores was used as the sample solution.

2) Preparation of Mirabegron standard solution

Accurately take 100 mg of Mirabegron Standard and place in a 100 mL volumetric flask. 50 mL was added, solubilized completely for 20 minutes by sonication, cooled to room temperature, and 50 mL was added to make 100 mL. This was diluted with an appropriate amount of mobile phase to prepare a standard solution of 1,000 μg / mL.

3) Mirabegron HPLC Analysis Conditions

HPLC analysis was performed on the Mirabegron under the following conditions, and the results are shown in FIG. 3.

Mobile phase: used as a 3: 7 (v / v) mixture of acetonitrile and 0.01 M potassium dihydrogen phosphate.

Column: Aegispak 5μιη C18-L or similar column, 150 x 4.6mm

Column temperature: 30 ° C

Detector: UV 249 nm

Flow rate: 1.0 mL / min

Injection volume: 20 μL

As a result, as can be seen in Figure 3, it was confirmed that the disintegration and dissolution pattern can be variously implemented by controlling the ratio of the release control mechanism such as hydroxypropyl cellulose and the erosion control mechanism such as low-substituted-hydroxypropyl cellulose. .

Experimental Example 4: Dissolution test of the sustained-release sustained-release tablet according to Examples 5-7

1) Preparation of Test Solution

From Examples 5 to 7, each of the amount corresponding to 50 mg of Mirabegron + 4 mg of pesoterodine was taken from each of the samples. Using eluent 900 mL of pH 6.8 buffer, three samples from each solution were carried out, and the dissolution test was performed at 37 rpm at 75 rpm according to the second dissolution test method. After 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, and 20 hours, 3 mL of eluate was taken and filtered through a membrane filter having a 0.45 μm pore as a sample solution. .

2) Preparation of Pesoterodine Standard Solution

5 mg of the pesoterodine standard were accurately taken and placed in a 100 mL volumetric flask. 50 mL was added, sonicated for 20 minutes, completely dissolved, cooled to room temperature, and 50 mL was added to make 100 mL. This was diluted with an appropriate amount of mobile phase to prepare a standard solution of 50 μg / mL.

3) Pesoterodine HPLC Analysis Conditions

Mobile phase: acetonitrile, purified water, trifluoro acetic acid 550: 450: 1 (v / v) mixed solution.

Column: Waters spherisorb S5CN 5 μm or similar column, 250 × 4.6 mm

Column temperature: 35 ° C

Detector: UV 220 nm

Flow rate: 0.8 mL / min

Injection volume: 50 μL

Mirabegron standard solution preparation and HPLC analysis conditions are the same as in Test Example 3, the analysis results are shown in Figures 4 and 5.

As a result, as can be seen in Figure 4, it was confirmed that the disintegration and dissolution pattern can be adjusted by adjusting the ratio of the release control mechanism such as hydroxypropyl cellulose and the erosion control base such as low-substituted-hydroxypropyl cellulose.

In addition, as can be seen in Figure 5, by adding a water-soluble gelling agent to form a swellable release layer was confirmed that the disintegration and elution pattern can be controlled relatively uniform regardless of the composition change of the sustained release layer of Mirabegron.

Experimental Example 5: Elution comparison test of the sustained-release bilayer tablet of Example 7 and Comparative Examples 1 and 2

Mirabegron and pesoterodine sample preparation, and standard solution preparation, HPLC analysis conditions are the same as in Test Example 4, the analysis results are shown in Figures 6 and 7.

In addition, the external appearance of the sustained-release bilayer tablet (Example 7) of Example 7 during elution is shown in FIG.

As a result, as can be seen in Figures 6 and 7, in the case of Example 7 bilayer tablets, it was confirmed that the dissolution rate of the Mirabegron layer was released at a rate equivalent to that of Comparative Example 1. In the case of the pesoterodine layer of Example 7, it was confirmed that the drug was released at the same rate as in Comparative Example 2.

Claims (13)

An erosive first layer comprising a mirabegron and an emission control mechanism; And
A swellable second layer comprising pesoterodine and a water-soluble gelling agent;
As a sustained release bilayer tablet,
The release controlling agent is hydroxypropyl cellulose, low-substituted-hydroxypropyl cellulose, or a mixture thereof,
The water-soluble gelling agent is hydroxypropyl methyl cellulose,
Sustained release bilayer tablets.
delete delete The method of claim 1,
Wherein the first layer comprises 10 to 100mg of Mirabegron
Sustained release bilayer tablets.
The method of claim 1,
Wherein the first layer comprises 150 to 200 mg of a release control mechanism.
Sustained release bilayer tablets.
The method of claim 1,
Wherein the second layer comprises 2 to 10 mg of pesoterodine.
Sustained release bilayer tablets.
The method of claim 1,
Wherein the second layer comprises 50 to 150 mg of a water-soluble gelling agent.
Sustained release bilayer tablets.
The method of claim 1,
The first layer further comprises one or more additives selected from the group consisting of magnesium stearate, ferric oxide red, polyethylene oxide and poloxamer
Sustained release bilayer tablets.
The method of claim 1,
The second layer further comprises one or more additives selected from the group consisting of erythritol, rudipress, compritol and talc.
Sustained release bilayer tablets.
The method of claim 1,
The average diameter of the sustained release bilayer tablet is 10 to 15mm
Sustained release bilayer tablets.
A first step of mixing and tableting granules, powder or granulated powder of the first layer of erosion; And
A second step of tableting by adding granules, powder or granulated powder of the swellable second layer on the tablet tableted in the first step; Consisting of
A method for producing a sustained release bilayer tablet according to any one of claims 1 and 4 to 9.
The method of claim 11,
The first step is to tablet at a pressure of 0.3 to 0.8 ton / m ²
Method for producing a sustained release bilayer tablet.
The method of claim 11,
The second step is to tablet at a pressure of 0.9 to 1.5 ton / m ²
Method for producing a sustained release bilayer tablet.

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