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Title:
PHARMACEUTICAL COMPOSITION COMPRISING MIRABEGRON AND PROCESS FOR MANUFACTURING THE SAME
Document Type and Number:
WIPO Patent Application WO/2021/069944
Kind Code:
A1
Abstract:
The present invention relates to a pharmaceutical composition comprising mirabegron and to a process for manufacturing the same. The pharmaceutical composition includes one or a addition second polyethylene oxide as a release-controlling agent and excipients antioxidant, diluents and lubricant. The granules are received by a dry granulation process. The pharmaceutical composition according to the present invention has advantages as improved stability, release of mirabegron at a constant rate, and small dissolution deviation among tablets. The tablets are manufactured in the simpler and more economical process.

Inventors:
HONG HYE SUK (KR)
HA SONG YI (KR)
GUPTA VIJENDER (TW)
ABRAHAM JAYA (IN)
CHANDAK ABHAYKUMAR (RO)
PARK SE HONG (KR)
LEE SEUL KI (KR)
Application Number:
PCT/IB2019/001001
Publication Date:
April 15, 2021
Filing Date:
October 09, 2019
Export Citation:
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Assignee:
ALVOGEN KOREA CO LTD (KR)
International Classes:
A61K9/20; A61P13/10
Foreign References:
KR101937713B12019-01-14
KR20180106185A2018-10-01
JP2016188181A2016-11-04
JP2017048136A2017-03-09
KR20050107298A2005-11-11
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Claims:
PATENT CLAIMS

1. A pharmaceutical composition comprising mirabegron, a more specifically of control release tablet, including as excipients polyethylene oxide, butylhydroxytoluene and a lubricant, characterized in that the pharmaceutical composition also includes a diluent, the polyethylene oxide having an average molecular weight of 100,000 to 900,000, the lubricant is magnesium stearate, and a ratio between the components of the composition as a percentage of the total weight of the tablet is as follows: from 5 to 22% mirabegron, from 40 to 90% polyethylene oxide, from 0.01 to 2% butylhydroxytoluene, from 10 to 25% diluent and from 0.05 to 4% magnesium stearate.

2. A pharmaceutical composition comprising mirabegron according to claim 1, where the polyethylene oxide is with an average molecular weight 300,000 and in an amount from 50 to 75%, more preferably 61%.

3. A pharmaceutical composition comprising mirabegron according to claims 1 and 2, where the pharmaceutical composition includes in additional from 1 to 30%, more preferable from 2 to 20% a polyethylene oxide with an average molecular weight from 2 million to 8 million.

4. A pharmaceutical composition of mirabegron according to claims from 1 and 3, where the pharmaceutical composition includes polyethylene oxide with an average molecular weight of 300,000 in the amount 55% and polyethylene oxide with an average molecular weight of 7 million in an amount 6,4%

5. A pharmaceutical composition comprising mirabegron according to claims 1 to 4, where the diluent is selected from the group consisting of microcrystalline cellulose, low substituted hydroxypropyl cellulose, starch, and calcium phosphate, and preferably is microcrystalline cellulose.

6. Process of production of a pharmaceutical composition according to claims from 1 to 5, characterized with that the mirabegron or a pharmaceutically acceptable salt thereof, the polyethylene oxide, the microcrystalline cellulose, the butylhydroxytoluene and a part of magnesium stearate is blended, the mixture obtained is compacted to prepare of dry granules, and the dry granules obtained are lubricated with the rest of magnesium stearate and is tableted.

AMENDED CLAIMS received by the International Bureau on 27 January 2021 (27.01.21)

1. A pharmaceutical composition, characterized by comprising: mirabegron or a pharmaceutically acceptable salt thereof as an active ingredient and polyethylene oxide as a release-controlling agent, and wherein the composition is free of hydrophilic materials.

2. The pharmaceutical composition according to claim 1, wherein the polyethylene oxide is polyethylene oxide with an average molecular weight of 100,000 to 900,000, included in the amount of 40 to 90%, preferably 50 to 75% by weight based on the total weight of the pharmaceutical composition.

3. The pharmaceutical composition according to claim 2, characterized in that it contains polyethylene oxide with average molecular weight 300,000 in the amount of 40 to 90%, preferably 50 to 75% by weight based on the total weight of the pharmaceutical composition.

4. The pharmaceutical composition according to claim 1 , wherein the polyethylene oxide includes polyethylene oxide with an average molecular weight of 100,000 to 900,000 and polyethylene oxide with an average molecular weight of 2 million to 8 million.

5. The pharmaceutical composition according to claim 4, wherein the polyethylene oxide with the average molecular weight of 100,000 to 900,000 is in the amount of 40 to 90%, preferably 50 to 75% by weight based on the total weight of the pharmaceutical composition, and polyethylene oxide with the average molecular weight of 2 million to 8 million is in an amount of 1 to 30%, preferably 2 to 20% by weight based on the total weight of the pharmaceutical composition.

6. The pharmaceutical composition according to claim 5, characterized in that it contains polyethylene oxide with the average molecular weight of 300,000 in the amount 55% and polyethylene oxide with an average molecular weight of 7 million in an amount 6,4%.

7. The pharmaceutical composition of any one of claims 1 to 6, characterized by further comprising one or more excipients from the group consisting of microcrystalline cellulose, butylhydroxytoluene and magnesium stearate.

8. The pharmaceutical composition according to any one of the preceding claims, which is a tablet comprising: dry granules, wherein the dry granules comprise mirabegron or a pharmaceutically acceptable salt thereof as an active ingredient and polyethylene oxide as a release-controlling agent, wherein the dry granules are free of hydrophilic materials.

9. The pharmaceutical composition comprising mirabegron according to claim 1, more specifically a controlled release tablet, including as excipients polyethylene oxide, butylhydroxytoluene and a lubricant, characterized in that the pharmaceutical composition also includes a diluent, the polyethylene oxide having an average molecular weight of 100,000 to 900,000, the lubricant is magnesium stearate, and a ratio between the components of the composition as a percentage of the total weight of the tablet is as follows: from 5 to 22% mirabegron, from 40 to 90% polyethylene oxide, from 0.01 to 2% butylhydroxytoluene, from 10 to 25% diluent and from 0.05 to 4% magnesium stearate.

10. The pharmaceutical composition comprising mirabegron according to claim 9, wherein the polyethylene oxide is with an average molecular weight 300,000 and in an amount from 50 to 75%, more preferably 61%.

11. The pharmaceutical composition comprising mirabegron according to claims 9 and 10, wherein the pharmaceutical composition includes in additional from 1 to 30%, more preferable from 2 to 20% a polyethylene oxide with an average molecular weight from 2 million to 8 million.

12. The pharmaceutical composition of mirabegron according to claim 11, where the pharmaceutical composition includes polyethylene oxide with an average molecular weight of 300,000 in the amount 55% and polyethylene oxide with an average molecular weight of 7 million in an amount 6,4%.

13. The pharmaceutical composition comprising mirabegron according to claims 9 to 12, where the diluent is selected from the group consisting of microcrystalline cellulose, low substituted hydroxypropyl cellulose, starch, and calcium phosphate, and preferably is microcrystalline cellulose.

14. A process for manufacturing a pharmaceutical composition according to any one of the preceding claims, characterized by comprising: blending mirabegron or a pharmaceutically acceptable salt thereof, polyethylene oxide, microcrystalline cellulose, butylhydroxytoluene and magnesium stearate; compacting the blend to prepare dry granules; and blending the dry granules and magnesium stearate and tableting them.

Description:
Pharmaceutical composition comprising mirabegron and process for manufacturing the same

TECHNICAL FIELDS

The present invention relates to a pharmaceutical composition comprising mirabegron, more specifically of a control release tablet and a process for manufacturing the same, which is used in pharmacy and medicine, in particular as beta 3 -adrenoceptor agonist, for reduces the activity of an overactive bladder and the related symptoms.

BACKGROUND

Mirabegron is a monocarboxylic acid amide first discribed in PCT application WO 9920607. It has protected as active compound useful for the treatment of diabetes ellitus, but the initial clinical development program for examination of an indication of type 2 diabetes mellitus was discontinued due to absence of efficacy. (Assessment report EMA/706651/2012) Under the PCT application W02004041276, Astellas Pharma protect new use of mirabegron as a therapeutic agent with overactive as a result for bening prostatic hyperplasia, accompanied by urindry urgency, urinary incontinence and pollakiuria. This application describes a pharmaceutical composition containing as active ingredient mirabegron in the form of solid conventional compositions for oral administration, which include at least one inert excipient such a lactose, mannitol, glucose HPMC, microcrystalline cellulose, starch, PVP and magnesium metasillicate aluminate.The composition may contain also an inert additive as lubricant , disintegrating agent, solubilizing agentand.The tablet is produced by a common method, and tablet core may be coated with sugar coat or with an intragastric or enteric coating agent.

The disadvantage of this pharmaceutical composition is that its pharmacokinetic data unexpectedly varied according to the presence or absence of the intake of food.

PCT application W02010038690 describes a sustained release tablet, which is prepared by using a OCAS® system formulation technique for reduce or avoid changes in pharmacokinetics such as AUC or Cmax accompanied by food intake. The pharmaceutical composition indicated in this application include at least one hydrogel-forming polymer having an average molecular weight of approximately 100,000 or more and at least one penetration additive selected from the group consisting of polyethylene glycol, polyvinylpyrrolidone, D-mannitol, lactose, sucrose, sodium chloride, and polyoxyethylene or polyoxypropylene glycol. The hydrogel-forming polymer is one compound, or two or more compounds selected from the group consisting of polyethylene oxide, hydoxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose sodium, hydroxyethyl cellulose, and a carboxyvinyl polymer. The composition includes also at least one antioxidant, which can be one compound, or two or more compounds selected from the group consisting of butyl hydroxytoluene, propyl gallate, and sodium ascorbate. These tablets are produced under wet granulation. It is known that the mirabegron is marketed as Betmiga, prolong- release film coated tablet containing 25 and 50 mg of mirabegron as the active substance. Originator Astellas Pharma on the base of results of the experimental studies use OCAS as modified release platform. The OCAS is a hydrophilic gel forming matrix tablet formulation, composed of active substance and hydroxypropylcellulose as hydogel-forming polymer and penetration agent hydrophilic polymers- macrogols with molecular-weight 8000 and 2 000 OOO.The tablet core include also the following excipients: an antioxidant as butylhydroxytoluene and magnesium stearate as lubricant. (EMA, SmPC of Betmiga, dated 02. April 2019)

The patent application EP3292864 discribes a modified release tablet composition comprising: 5 to 25 wt% mirabegron with respect to the total weight of the uncoated tablet polyethylene oxide (PEO) having an average molecular weight of approximately 7,000,000 and polyethylene glycol (PEG) having an average molecular weight of approximately 6000 to 10000, preferably 8000, wherein the weight ratio PEO to PEG ranges from 1:3 to 1:4.5. As additional excipients, the tablets include a binder in an amount of from 1% to 5 wt% with respect to the total weight of the uncoated tablet, a lubricant in an amount from 0.05% to 5wt% with respect to the total weight of the uncoated tablet and diluent MCC, preferably is in an amount 5 to 25% with respect to the total weight of the uncoated tablet. This tablet has been produced under dry granulation process.

Some patents and applications describe alsoa pharmaceutical composition relates to a mirabegro containing pharmaceutical preparation with extended active principle release. The release controlling agent is a hydrogel forming polymer at least one selected from polyethylene oxide, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, and hydroxyethyl cellulose. The additive for infiltrating water into the formulation is a hydrophilic base as PEG or PVP. (WO2017038281; WO2019013583; CN107397733; CN106361715; CN106176650; CN104352475) WO2018108939 described a solid oral pharmaceutical dosage form with extended active principle release comprising mirabegron. In order to provide a bioequivalent dosage form of the generic ty e the matrix comprises a hydrogel-forming agent selected from the group consisting of a mixture of at least two hydroxypropyl methylcelluloses that are different from each other, selected from alginate, alginic acid, poly(meth)acrylate-based polymer and carrageena. The matrix is free of PEO and antioxidants and weight ration of active ingredient to the hydrogel forming agent is in a range 1:1 to 1:50. The dosage form includes in addition filler, a binder, a disintegrant and a lubricant as pharmaceutically acceptable excipients. Dosage form is optionally with a film coating .Method of production is dry granulation process.

KR20180106924 relates to a controlled-release pharmaceutical composition, where PEO is a combination of PEO having viscosity of 30 cps to 17600 cps in an amount 10 to 50% and PEO having an average molecular weight aver 100000 to 900000 in an amount 20 to 70 % by weight relative to total weight of the tablet. The acceptable excipients are glidants, a sustained release base and water insoluble solubilizer.

WO2018169325 is related to a controlled release tablets of mirabegron, which include as release controlling agent 300 000 PEO and 1M PEO mixed in a ration from 1:0,1 to 1:5, 5%, a hydrophilic base selected from PEG,PVP, sugar and derivatives, organic acid, anino acid as well as other pharmaceutically acceptable additives. KR20180104259 relates to a release-controlled pharmaceutical composition comprising mirabegron and hydrophobic non-hydrogel matrices composed of at least one sustained release agent selected from the group consisting glyceryl behenat and cured Castrol oil in an amount from 10 to 90 w%, and non soluble desintegrant. The pharmaceutical form is prepared by wet granulation process. KR101937713 provides a control release film coated tablet contains mirabegron as active component and a controlled release agent. The controlled release agent is a polyethylene oxide with average molecular weight between 100000 and 1 million or a combination from polyethylene oxide having average molecular weight of 100000 to less 500000 and polyethylene oxide of an average molecular weight of 500000 to less than 1 million and it is in an amount 60-90 wt%. The composition includes also a binder with quantity 1 to 5% by weight, an antioxidant from 0,1 to 1% by weight and a lubricant from 1 to 6 % by weight. The lubricant comprises 1-3 wt % silicon oxide and 1-3 wt % magnesium stearate, and the release controlling agent does not include additives for invading water inside the formulation. The process of preparation of the tablet core is a wet granulation process, using as volatile solvent is ethanol. The disadvantages of this pharmaceutical composition is stability issues due to presence of moisture and organic solvent may occur as well as the long period of manufacturing time and the requirement of use of expensive facilities. The task of the invention is developing a mirabegron pharmaceutical composition allows to reduce the generation of related substances, to ensuring stability during the manufacturing and after the packaging process and during storage, to garantee released the drug at a constant rate, to kept the dissolution rate consistent from one formulation to another, to keep the efficacy of the drug consistent for preventing adverse effects as well as the pharmaceutical composition to be produced by simple and economical process.

DISCLOSURE OF INVENTION To accomplish the above-mentioned purposes, the present invention provides a pharmaceutical composition, comprising mirabegron or pharmaceutically acceptable salts thereof as an active ingredient, a release-controlling agent polyethylene oxide and pharmaceutically acceptable excipients. Polyethylene oxide may have polyethylene oxide with an average molecular weight of 100,000 to 900,000, included in the amount of 40 to 90%, preferably 50 to 75% by weight based on the total weight of the pharmaceutical composition.

In one preferred embodiment a release-controlling agent polyethylene oxide is polyethylene oxide with an average molecular weight of 300,000 and an amount 61% by weight based on the total weight of the pharmaceutical composition.

In one embodiment of the invention, the pharmaceutical composition may include as a release-controlling agent a polyethylene oxide with an average molecular weight of 100,000 to 900,000 and polyethylene oxide with an average molecular weight of 2 million to 8 million at the same time. It is preferred polyethylene oxide with the average molecular weight of 100,000 to 900,000 to be in an amount of 40 to 90, more preferably 50 to 75% by weight based on the total weight of the pharmaceutical composition, and polyethylene oxide with the average molecular weight of 2 million to 8 million is in an amount of 1 to 30%, preferably 2 to 20% by weight based on the total weight of the pharmaceutical composition.

In one preferred embodiment of the invention, the pharmaceutical composition as a the release-controlling agent comprises polyethylene oxide with an average molecular weight of 300,000 in the amount 55% and polyethylene oxide with an average molecular weight of 7 million in an amount 6,4% .

If the amount of a polyethylene oxide exceeds the above, the release of mirabegron is excessively inhibited, resulting in low absorption into the body. If the amount of a polyethylene oxide is not sufficient, the rapid release of mirabegron can cause a problem where pharmacokinetic data of the drug significantly has ranged depending on the presence or absence of the intake of food.

As pharmaceutically acceptable excipients in the pharmaceutical composition of the invention is used antioxidant, diluent and lubricant. As the antioxidant may be used butylhydroxytoluene (BHT), propyl gallate (PG), butylhydroxyanisole (BHA), ascorbic acid, sodium ascorbate, erythorbic acid, sodium nitrite, sodium hydrogen sulfite, sodium pyrosulfite, and citric acid, and preferably, butylhydroxytoluene (BHT). The antioxidant may be in the amount of 0.01 to 2% by weight based on the total weight of the pharmaceutical composition. The lubricant is preferable to be in the amount of 0.05 to 4% by weight based on the total weight of the pharmaceutical composition. The lubricant may be selected from the group of compounds consisting of magnesium stearate, talc, hydrogenated castor oil, calcium stearate and silicon dioxide, and, preferably, magnesium stearate.

By using a lubricant in the above range, it can play a role in improving flowability during the manufacturing of granules, in preventing the sticking to devices such as punches or rollers, and in reducing resistance when withdrawing the granules from the devices.

It is preferred that the diluent to be in the amount of 10 to 25 % by weight based on the total weight of the pharmaceutical composition to ensure uniform flow, desirable compression properties, and content uniformity is contained . The diluent may be selected from the group consisting of microcrystalline cellulose, low substituted hydroxypropyl cellulose, starch, and calcium phosphate, and preferably microcrystalline cellulose.

The pharmaceutical composition of the present invention does not include hydrophilic materials capable of invading water inside the formulation.

In other aspect, the invention is directed to the process of production of the pharmaceutical composition of mirabegron. The tablets are produced by using a dry granulation process.

In the specification of the present application, the term "dry granules" refers to granules that are prepared substantially without using any granulating solvents such as water or ethanol. On the other hand, the term "wet granules" refers to granules that are prepared by using a solution as a binding agent to agglomerate wetted mass during the manufacturing process, and then drying the wetted mass at appropriate temperature and time using a tray dryer or a fluid bed dryer followed by milling.

The process of production of the pharmaceutical composition of mirabegron, according to the invention comprises the following steps: -blending of mirabegron or a pharmaceutically acceptable salt thereof, the polyethylene oxide, the microcrystalline cellulose, the butylhydroxytoluene and part of magnesium stearate;

-compacting the mixture to preparation of dry granules; and

-lubricating the dry granules received with the rest quantity of magnesium stearate; and -tableting the received blend.

In the present invention, the dry granulation may be carried out by roller compaction or slugging, and preferably, by roller compaction. The roller compaction refers to a method of making granules by compressing powders at a constant pressure while passing them through two rollers. The roller-compacted blends may be subjected to milling or sieving to obtain a suitable size of granule. The milling process is milling or sieving the granules to a suitable particle size and may utilize fitz-mill, co-mill, oscillator, etc. The milled particles may be applied through a sieve or mesh screen to obtain the granules with desired particle sizes.

The dry granulation method according to the present invention has advantages of being economical and productive due to the simple manufacturing process and short manufacturing time, and not having problems such as stability caused by water or organic solvents. Further, in the present invention, it was found that manufacturing mirabegron tablets using direct compression method is not suitable for mass production due to the poor content uniformity of tablets and flow ability of the powder.

The advantage of the invention is that the developed pharmaceutical composition allows to reduce the generation of related substances, thereby ensuring stability during the manufacturing and after the packaging process and also allows long-term storage, the drug is released at a constant rate, the dissolution rate is kept consistent from one formulation to another, keeping the efficacy of the drug consistent, preventing adverse effects and the pharmaceutical composition is produced by simple, and economical process.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 shows the results of dissolution tests for tablets of Examples 3 to 5 comprising different amounts of polyethylene oxide with an average molecular weight of 300,000 as a release-controlling agent.

Fig. 2 shows the results of dissolution tests for tablets of Examples 10 to 14 comprising different amounts of polyethylene oxide with an average molecular weight of 100,000 to 300,000 and polyethylene oxide with an average molecular weight of 2 to 7 million, as a releasecontrolling agent. Fig. 3 is a comparative evaluation of the dissolution rate of mirabegron tablets manufactured by dry granulation method (Example 1), direct compression method (Example 6) and wet granulation method (Example 7). EXAMPLES

The examples of the present invention are provided to illustrate the present invention more fully. However, the examples according to the present invention may be modified in many other ways and are in no way intended to be limiting the scope of the present invention.

Example 1. Preparation of mirabegron tablets containing 50 mg mirabegron, according to the invention

The tablet formulation containing 50 mg of active substance mirabegron is prepared using the following components:

50 mg mirabegron, 36, 5 mg microcrystalline cellulose, and 2 mg magnesium stearate were pre blended. From the mixture received granules were formed using a roller compactor (Freund TF- 156). Granules were also formed from the mixture prepared by blending of 25 mg Polyethylene oxide 7M, 19 mg Polyethylene oxide 900K, 79 mg PEG8000, 34 mg Microcrystalline cellulose, 1,5 mg Butylhydroxytoluene and 1,5 mg Magnesium stearate in the same manner. Two individually received granules were lubricated with 1,5 mg magnesium stearate and tableted with a rotary tablet press to produce tablets. Examples 2 to 5. Preparation of tablets containing 50 mg mirabegron with different in quantity excipients, according to the invention

As shown in the Table above, the appropriate quantity of mirabegron, microcrystalline cellulose, polyethylene oxide, butylhydroxytoluene, and magnesium stearate were blended, and granules were formed using a roller compactor (Freund TF-156). The granules were milled, and then lubricated using magnesium stearate. They were tableted with a rotary tablet press to produce tablets.

Evaluation of dissolution properties of the pharmaceutical composition according depending on the amounts of polyethylene oxide in the composition

The dissolution rates of the reference drug (Betmiga PR tablet) and the tablets of Examples 3 to 5 which include different amount of polyerhylene oxide were evaluated. The dissolution test was carried out in accordance with the padle mehod of the USP dissolution test (50 rpm, pH 6,8 phosphate buffer 900 ml). Four samples from each type tablets were tested to the obtain the average value and deviation, and the results received are shown in the Table 1 and shown graphically in the Fig.1.

"able 1

The determination of the dissolution rates indicated that all the tablets of Examples 3 to 5 showed the dissolution patterns close to the zero-order rate up to six hours.

The tablets of Example 3, which comprise polyethylene oxide with the molecular weight of 300,000 (PEO 300K) as a release-controlling agent in the amount of about 75% by weight of the tablets represented a tendency to decrease the dissolution rates after six hours.

The tablets of Example 4 comprising PEO 300K in the amount of about 54% by weight of the tablets provided the greater dissolution deviation than the other tablets.

On the other hand, the tablets of Example 5 comprising PEO 300K in the amount of about 61% by weight of the tablets showed the dissolution rate that were similar to those of the reference drug, and the dissolution rate is maintained consistently up to 12 hours, with the small dissolution deviation.

The tablets of mirabegron with the composition, according to the invention, but received by using are different processes of production was prepared for evaluation of importance of the process used for production of tablets with good uniformity and flowability as well as of dissolution properties similar essentially to the comersial available tablets Betmiga PR, as follows:

Example 6. Preparation of mirabegron tablets by direct compression method.

50 mg Mirabegron, 25 mg polyethylene oxide 7M , 164,6 mg polyethylene glycol, 7,5 mg low substituted hydroxypropylcellulose and 0,4 mg butylhydroxytoluene were uniformly blended, and further lubricated by using 2,5 mg magnesium stearate. The final blends were tableted with a rotary tablet press to produce tablets.

Evaluation of content uniformity and flowability of mirabegron tablets from Example 6 prepared by direct compression method

In order to determine the content uniformity of mirabegron tablets prepared by a direct compression method, three compressed products were each weighed, and the content uniformity was measured under the following condition in accordance with the test method for content uniformity in the uniformity test of formulations among the general test methods of the Korean Pharmacopoeia.

<Condition for uniformity test>

©Detector: UV spectrophotometer (detection wavelength: 250 nm)

©Column: Diameter4.6 x 150 mm, 3.5 p or equivalent column ©Mobile phase: 10 mM Phosphate buffer (pH 3.0), acetonitrile

In addition, before compression, lOOg of the blends from each of the examples and the comparative examples were accurately weighed and carefully placed in a 250mL measuring cylinder so as not to be compacted, and then the apparent volume was measured. The tapped volume was measured by tapping the measuring cylinder on a tap density tester. By these measurements, Carr's Index (Carr's compressibility) was calculated according to the follow formula:

Carr's Index = 100* (TD -BD) / TD where TD is tapped density (g/mL), BD is apparent density (g/mL)

The measured values of Comparative Example 1 according to the method above are represented in Table 2 below, and the criteria for measuring flowability using Carr's Index are shown in Table 3.

Table 2

Table 3

The tablets of Example 6 prepared by direct compression method failed to show uniform content values with a minimum content of 95.3% and a maximum content of 110.9%. Carr'slndex was determined as 31 to 38%, indicating very poor flowability according to the criteria in Table 3.

Finally, it was found that the mirabegron tablets produced by direct compression method are disadvantageous for mass production due to poor content uniformity of the drug and poor flow of the granules. Example 7 to 10. Preparation of mirabegron tablets by wet granulation method

Mirabegron tablets were prepared with the ingredients and quantities listed in the Table below. Granules were prepared by blending the ingredients from the pre-blending portion followed by wet massing by addition of the binding solution, dried and then milled. The final granules were prepared by mixing with the ingredients from the post-blending portion. The final granules were lubricated with magnesium stearate and then tableted with a rotary tablet press to produce tablets. Comparative evaluation tests of the stability of mirabegron tablets/detection of related substances generation / depending on the manufacturing method of mirabegron tablets and the presence or absence of hydrophilic materials through which may capable of invading water in the formulation.

For comparative evaluation of the stability of mirabegron tablets/detection of related substances generation /were conducted comparative Test of Stability of tablets with the composition indicated in the Example 2, produced by dry granulation process and the tablets of Examples 8, 9 and 10, produced by wet granulation process.

With Al-Al blister packaged tablets, the generation of unknown related substances during the storage under the stress test condition (temperature 60°C, humidity 80%, 1 month) and the accelerated test condition (temperature 40°C, humidity 75%, 3 months) were evaluated under the following test condition, and the results are described in Tables 7 and 8.

<Condition for detection of related substances>

(D Detector: UV spectrophotometer (detection wavelength: 250 nm) ©Column: Diameter 150 mm L. x 4.6 mm I.D., 3.5 pm or equivalent column

©Mobile phase: 10 mM Potassium dihydrogen phosphate solution (pH 3.0), methanol

Table 4

Table 5 As shown in Tables 4 and 5 above, the generation of related substances was found to be lowest in tablets of Example 2, which contained only polyethylene oxide as a release-controlling agent and were manufactured by dry granulation method. On the other hand, tablets of Examples 8 to 10, which in addition to polyethylene oxide, further included polyethylene glycol (Examples 8 and 10) or the sugar alcohol isomalt (Example 9) as hydrophilic materials and all of them were prepared by wet granulation method, showed the higher generation of related substances under both the stress and accelerated test conditions.

Thus, it was established that mirabegron formulations with excellent stability can be obtained by manufacturing tablets by using dry granulation method without containing in the composition hydrophilic materials. Comparative evaluation of dissolution properties, according to different methods for manufacturing tablets, in particular the tablets received by dry granulation method /Example 1/, direct compression method /Example 6/ and wet granulation method /Example

7/.

The dissolution test was conducted on the tablets of Example 1, Examples 6 and 7 in order to identify the dissolution pattern according to different methods for manufacturing tablets. The dissolution test was carried out in accordance with the paddle method of the USP dissolution test (50rpm, pH 6.8 phosphate buffer 900ml). Four samples from each case were tested to obtain the average value and deviation, and the results were shown in Table 6 and Fig. 1.

Table 6

As show from Table 6 above and Fig. 3, it was found that the tablets of Example 1 prepared by dry granulation method released mirabegron at a zero-order rate for nearly eight hours and also had small dissolution deviation. In contrast, as shown in the test results of Examples 6 and 7, the tablets prepared from direct compression method or wet granulation method failed to maintain the zero-order rate of dissolution pattern.

Therefore, it was concluded that the mirabegron tablets manufactured by dry granulation method show a similar rate (slope) of dissolution pattern to that of commercially available Betmiga PR tablets as well as small dissolution deviation.

Examples 10 to 14. Preparation of mirabegron tablets, where the control release agent is combination of polyethylene oxides with different average molecular weight

In the same way as in Examples 2 to 5, mirabegron tablets in Examples 10 to 14 were prepared by dry granulation method. Tablets comprise polyethylene oxide with the molecular weight of 300,000 (PEO 300K) and 7 million (PEO 7M) together as a release-controlling agent in Examples 6, 7 and 8. Mirabegron tablets in Example 9 comprised PEO 100K (molecular weight of 100,000) and PEO 900K (molecular weight of 900,000), and Example 10 was composed with a combination of PEO 100K and PEO 2M (molecular weight of 2 million). The composition and quantities are explained in Table below.

Evaluation of dissolution properties according to the amount of polyethylene oxide

The dissolution test was carried out for the reference drug (Betmiga PR tablets) and the tablets of Examples 10 to 12 in accordance with the paddle method in the USP dissolution test (200 rpm, pH 6.8 phosphate buffer 900 mL). Four samples from each case were tested to obtain the average value and deviation, and the results are shown in Table 7 and Fig. 2.

Table 7

The determination of the dissolution rates showed that the tablets of Example 12, which comprise PEO 300K in the amount of about 55% by weight of the tablets and PEO 7M in the amount of about 6.4% by weight of the tablets as a release-controlling agent, represented the dissolution rates that were similar to those of the reference drug and maintained consistently up to eight hours, and had the smaller dissolution deviation, as compared to the tablets of Examples 10 and 11 comprising less PEO 7M than those of Example 12. Examples 13 and 14 were used as the backup formulations comprising PEO 100K, 900K and PEO 2M and the dissolution rate of mirabegron was found to be similar to the dissolution rate of reference drug up to 8 hours.