EP4419087A1

EP4419087A1 - Pharmaceutical composition comprising mirabegron in matrix form

Info

Publication number: EP4419087A1
Application number: EP21968317.4A
Authority: EP
Inventors: Erol KIRESEPI; Ersin Yildirim
Original assignee: Santa Farma Ilac Sanayi AS
Current assignee: Santa Farma Ilac Sanayi AS
Priority date: 2021-12-15
Filing date: 2021-12-15
Publication date: 2024-08-28
Also published as: WO2023113706A1

Abstract

The present invention relates to a prolonged release formulation comprising mirabegron or a pharmaceutically acceptable salt thereof with at least two hydrogel forming agents and a binder to obtain improved release profile in three different physiological media of gastrointestinal tract for use in the treatment of overactive bladder.

Description

PHARMACEUTICAL COMPOSITION COMPRISING MIRABEGRON IN MATRIX

FORM

Field Of Invention

Background of the Invention

Overactive bladder is defined by The International Continence as urgency, with or without urgency incontinence, usually with frequency and nocturia. There is lack of information why overactive bladder occurs, but it is known that it involves detrusor overactivity which is responsible for feeling urgency by involving afferent signaling conveyed as bladder sensations.

There are many options for treatment of overactive bladder such as; bladder training and drug therapy using anticholinergic substances such as propiverine hydrochloride and oxybutynin hydrochloride have been mostly used at present. However, intractable cases and side effects could be occurred such as urinary dysfunction and dry mouth and, therefore, Mirabegron has been reported as one of the substance for the management of overactive bladder.

Mirabegron is a selective agonist for human beta 3 -adrenoceptor (beta 3 -AR) which is also dominant in the human detrusor muscle. However, Mirabegron has been firstly declared by the Astellas Pharma Inc to be used for the treatment for diabetes, due to having an activity of promoting insulin secretion and enhancing insulin sensitivity, and also having an antiobestic activity and an antihyperlipemic activity. But then, it has been reported that Mirabegron can be used as an overactive bladder, such as overactive bladder accompanied by prostatic hyperplasia, or overactive bladder accompanied by urinary urgency, urinary incontinence, and urinary frequency.

The chemical name of Mirabegron is 2-(2-Amino-l,3-thiazol-4-yl)-N-[4-(2-{ [(2R)-2-hydroxy- 2-phenylethyl] amino} ethyl) phenyl] acetamide and the empirical formula is C21H24N4O2S. The compound has a molecular weight of 396.506 g/mol. The structural formula of Mirabegron is shown in the Formula I.

Formula I

Mirabegron appears as a white crystalline powder and non-hygroscopic. It can freely soluble in dimethyl sulfoxide, soluble in methanol and soluble in water between neutral to acidic pH, thus it is categorized as BCS 3 Drug which exhibits high solubility and low permeability.

Mirabegron has one chiral center and exhibits stereoisomerism. The manufacture of the finish product consists of the R-enantiomer.

Mirabegron and its pharmaceutically acceptable salts thereof first have been described in EP1028111 numbered patent document by Yamanouchi Pharmaceutical Co.

EP1559427 numbered patent document was the first discloses a pharmaceutical composition comprising mirabegron that can be used as a therapeutic agent for overactive bladder, such as overactive bladder accompanied by prostatic hyperplasia, or overactive bladder accompanied by urinary urgency, urinary incontinence, and urinary frequency.

A pharmaceutical final product comprising mirabegron as an active substance was first approved in Japan and has been launched under the brand name of B ETANIS'®. In a similar way, it was commercially approved by the U.S. Food&Drug Administration in June 2012 and by European Medicines Agency in December 2012 and has been launched under the brand name of the MYRBETRIQ® in the United States and BETMIGA® in the Europe. All of the approved products are available as prolonged release tablet dosage form in the strengths of 25 mg and 50 mg of mirabegron for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency. Normally the patients are administered 1 prolonged-release tablet of 50 mg dose daily. However, the special patient population with renal insufficiency is administered 1 prolonged-release tablet of 25 mg dose daily.

Mirabegron in the prolonged released film coated tablet dosage form is designed to control the drug release from the tablet which lead to slower absorption rate in the gastrointestinal tract than immediate release formulations, even in fasted conditions, due to pharmacokinetic variation of mirabegron according to the presence or absence of food intake. For instance, the rate of decrease in Cmax and AUC after administration of 50 mg dose with high-fat meal is 45% and 17%, respectively. Moreover, the decrease in Cmax and AUC after administration of 50 mg dose with low-fat meal is 75% and 51%, respectively.

In the state of art there are many patents/patent applications which are summarized below.

EP2554168 relates to a sustained release hydrogel-forming formulation comprising mirabegron or a pharmaceutically acceptable salt thereof, hydrogel-forming polymer such as polyethylene oxide and hydroxypropyl cellulose and an additive such as polyethylene glycol that allows water to penetrate into the formulation to provide the dissolution rate of the mirabegron from the composition as 75% or less after 1.5 hours in pH 6.8. However, administration of polyethylene glycol can be hypersensitive or allergic for an increasing number of people.

EP2345410 relates to modified release pharmaceutical composition comprising mirabegron, at least one additive having a solubility such that the volume of water required for dissolving 1 g of the additive is 10 mL or less to ensure penetration of water into the pharmaceutical composition, and a hydrogel-forming polymer having an average molecular weight of approximately 100.000 or more, or a viscosity of 12 cP or more at a 5% aqueous solution at 25°C. Most of the presented examples in the document comprises polyethylene glycol that can lead allergic reactions.

EP3278801 relates to a pharmaceutical composition comprising a complex of mirabegron with sodium polystyrene sulfonate, a thickener, and a hydrophobic substance, wherein the hydrophobic substance is magnesium stearate and/or calcium stearate. The use of mirabegron in the manufacture of the present invention does not form any complex.

EP2832730 relates to a pharmaceutical composition for modified release comprising acid addition salt of alkyl sulfuric acid and mirabegron, and a base to mask the bitter taste of mirabegron for use in pediatric dosage forms and liquids.

WO201 1122523 relates to a multilayered pharmaceutical composition comprising mirabegron or a pharmaceutically acceptable salt thereof, and a carrier to provide the dissolution rate of mirabegron less than 85% after 30 minutes. The carrier used in the formulation to deliver mirabegron in controlled-release manner. EP3345600 relates to a pharmaceutical composition comprising amorphous form of mirabegron, hypromellose, and polyvinylpyrrolidone, wherein the spray-dried granulated product contains 100% or more by mass of the hypromellose, and the polyvinylpyrrolidone in total with respect to a content of the mirabegron. Mirabegron is used in amorphous form to overcome poor solubility in water.

W02019072404 relates to a pharmaceutical composition for modified release comprising; mirabegron presenting 5-25 wt% to the total weight of the uncoated tablet, a hydrogel forming polymer and an additive which is polyethylene glycol and manufactured by using dry granulation process.

EP3448366 relates to a pharmaceutical composition for modified release comprising; 5 to 25 wt% mirabegron, 15 to 40 wt% two types of polyethylene oxide and a microcrystalline cellulose used as water insoluble hydrophilic excipient.

EP3554480 relates to a solid pharmaceutical oral dosage form comprising mirabegron or a pharmaceutically acceptable salt thereof and hydrogel former which consists of at least two types of hydroxypropyl methylcellulose, alginate, alginic acid, poly (meth) acrylate-based polymer and carrageenan to provide the mirabegron in sustained release by releasing the 20% to 40% of mirabegron in 3 hours, 44% to 64% of mirabegron in 5 hours and more than 80% of mirabegron in 8.5 h in pH 6.8.

WO2018169325 relates to a controlled release pharmaceutical composition comprising mirabegron or a pharmaceutically acceptable salt thereof and two types of polyethylene oxide PEO100 and PEO 300.

Based on the prior art documents summarized above, the bioavailability of mirabegron is affected by the presence of food in the gastrointestinal tract. Thus, it is often formulated in composition comprising with hydrogel type polymer and an additive to provide prolonged release dosage form throughout the gastrointestinal tract wherein additive ensures the penetration of water into the core and contribute the forming gelling in the upper part of the gastrointestinal tract. These additives are generally polyethylene glycol or its derivatives.

Although, polyethylene glycols are inert and safe, small number of people experience hypersensitivity reactions to polyethylene glycols. In addition, polyethylene glycols are highly effective on pharmaceutical behavior of drug products. It is also observed that without using excipients stated as additive, the dissolution profile needs to be supported by using complexes or salts of mirabegron, amorphous form of mirabegron requiring additional excipients to overcome stability problems, high amounts of hydrogelforming polymers and designing non-conventional and not easy to use tablet technologies like multilayered tablet. In spite of all these, none of the prolonged release tablet formulation designs present a dissolution rate of more than 85% mirabegron release in 8.5 h both in three different gastrointestinal pH media simulating gastrointestinal (GI) tract.

In conclusion, the present invention that shows improved dissolution profile of mirabegron is obtained by using specified amount ratios of the hydrogel forming polymers and other pharmaceutically acceptable excipients which do not act as additive although being effective on release profile of mirabegron.

Summary of the Invention

The present object of this invention is to develop a pharmaceutical composition comprising therapeutically effective amount of mirabegron or one of its pharmaceutically acceptable salts, at least two hydrogel forming agents and binder to provide prolonged release dosage form with improved dissolution profile.

The object of the present invention is to provide a pharmaceutical composition comprising mirabegron in crystalline form.

Another object of the present invention relates to a pharmaceutical composition comprising mirabegron wherein the release of mirabegron is controlled by matrix core tablet.

Another object of the present invention relates to a pharmaceutical composition comprising mirabegron in the matrix core with at least two hydrogel forming agents, a binder and at least one pharmaceutically acceptable excipients in the specified amount ratio between the hydrogel forming agents with having stated physical properties such as molecular weight and viscosity contribute to form a gel layer to achieve prolonged release throughout the gastrointestinal tract.

Another object of the present invention relates to a pharmaceutical composition comprising one of the hydrogel forming agent which is polyalkylene oxide derivative having an average molecular weight of approximately 2,000,000 or a viscosity of 2000 to 4000 cP at a 2% aqueous solution at 25° C. Another object of the present invention relates to a pharmaceutical composition comprising the other hydrogel forming agent which is cellulose derivative having a viscosity within the range of 80 to 120 cP in 2% aqueous water at 20° C.

Further object of the present invention is related to a prolonged-release pharmaceutical composition comprising two different hydrogel forming agent in ratio of 4:3.

Further object of the present invention relates to a pharmaceutical composition comprising a binder in a specified amount range of between 5% - 10% wt by the total weight of the composition.

In the further object of the present invention, a prolonged-release pharmaceutical composition comprising mirabegron with at least two hydrogel forming agents in amount ratio of 4:3, binder in a specified amount range of between 5% - 10% wt by the total weight of the composition and one or more pharmaceutically acceptable excipient releases more than 85% of mirabegron in 8.5 hours in 0.1N HC1, pH 4.5, pH 6.8 buffer solutions simulating gastrointestinal (GI) tract conditions at 37±0.5°C using USP type I (basket) apparatus rotating at 100 rpm.

Detailed Description of the Invention

The present invention relates to a prolonged release formulation comprising mirabegron or one of its pharmaceutically acceptable salts thereof as active ingredient and one or more pharmaceutically acceptable excipient.

Mirabegron is a human P3 -adrenoceptor agonist which has been used as a therapeutic agent for overactive bladder, such as overactive bladder accompanied by prostatic hyperplasia, or overactive bladder accompanied by urinary urgency, urinary incontinence, and urinary frequency.

According to the Biopharmaceutical Classification System (BCS), mirabegron is considered to be BCS Class 3 drugs, having a good solubility but poor permeability. Nevertheless, mirabegron presents poor solubility in water and aqueous solutions.

Mirabegron is known to have poor bioavailability and can be affected by many factors like dose and gender wherein its oral bioavailability is in the range from 29% to %35 for 25 mg and 35 mg respectively and women have higher bioavailability than men. Besides that, it is also known that the presence of food in the gastrointestinal tract restrict the bioavailability of mirabegron wherein the fat content of food is also effective. The maximum concentration (Cmax) and the area under the concentration-time curve (AUC) are reduced following high or low fat meal compared to fasting.

After oral administration of mirabegron from an immediate release dosage form, in fed state the absorption time is estimated approximately 4 hours. However, its terminal elimination halflife (ti/2) is quite long like about 50 hours.

Thus, in the preferred embodiment, the release profile of mirabegron is extended to avoid the effect of food on bioavailability wherein the absorption time about 4 h in fed state can be reached with prolonged period of time for at least about 12 hours, as an indicative 8.5 hour is accepted critical.

The term "prolonged release" herein refers to any composition or dosage form which comprises active ingredient and which is designed to achieve or extend therapeutic effect by continuously releasing over an extended period of time after administration corresponding to immediate release dosage form administered by the same route.

In the embodiment of present invention, the term “prolonged release dosage form” involves a matrix form comprising homogenously dispersed the active ingredient throughout at least two hydrogel forming agents which ensure to control release rate of active ingredient by swelling to form a hydrogel layer allowing drug release through the outer surface of the gel.

In the embodiment of present invention, the soluble portion of the drug is released from swellable hydrophilic matrix form.

In the preferred embodiment of the present invention, at least two hydrogel forming agents may include, but are not limited to, polyethylene, polyethylene oxide, ethyl cellulose, hydroxypropyl methylcellulose and hydroxypropyl cellulose and their copolymers. Preferably, the hydrogel forming agents are selected as hydroxypropyl methylcellulose and polyethylene oxide.

Hydroxypropyl methylcellulose (HPMC) is a semi- synthetic derivative of cellulose with having rapid hydration, good compression and gelling characteristics. Thus, it is the most commonly used hydrophilic polymer in matrix systems. Also, its nontoxic property, easy of handling and compression and ability to present a large percent of drug make it an excellent excipient. Polyethylene oxide is polyalkylene oxide derivative with being a nonionic homopolymer of ethylene oxide which is represented by the formula [(OCthCPDn], wherein n represents the average number of oxy ethylene groups and varies from about 2,000 to 160,000, in which the molecular weight range of polyethylene oxide from 100,000 to 7,000,000 Da.

Polyethylene oxide is non-toxic, non-ionic, water-soluble polymers used in the development of controlled delivery systems, due to their hydrophilic character. It swells upon contact with body fluids and forms gel strength which leads to decrease the rate of diffusion of the drug.

There is a relationship between swelling capacity with viscosity grade for achieving desired prolonged release matrix formulations.

In the embodiment of present invention comprises hydroxypropyl methylcellulose having a viscosity within the range of 80 to 120 cP in 2% aqueous water at 20° C.

In the embodiment of present invention comprises polyethylene oxide having an average molecular weight of approximately 2,000,000 or a viscosity of 2000 to 4000 cP at a 2% aqueous solution at 25° C.

In the preferred embodiment of the present invention, the release profile of mirabegron is provided a prolonged release from the matrix form comprising at least two hydrogel forming agents for at least 8 h, preferably up to about 12 h, wherein the matrix composition does not comprise an additive acts a supporting agent for the penetration of water in to the matrix.

However, according to EP2345410 numbered document, any additive such as polyethylene glycol or mannitol is combined with at least one hydrogel forming polymer such as polyethylene oxide and hydroxypropyl methylcellulose, or combination thereof to obtain dissolution rate of mirabegron after 7 hours in pH 6.8 more than 75%. In the declared example, polyethylene glycol plays a crucial role for promoting pore formation in the polymeric matrices.

Although, polyethylene glycol is preferred in all pharmaceutical compositions, it is known it causes delayed or immediate hypersensitivity and changes in pharmacokinetic behavior during using as an additive of hydrophilic base.

Thus, the present invention come forward both of not using any additive such as polyethylene glycol or equivalence, and obtaining release of more than 85% of mirabegron after 8.5 hours in physiological media simulating gastrointestinal tract. In the preferred embodiment relates to the pharmaceutical composition comprising mirabegron combining with at least two hydrogel forming agents, binder, antioxidant, lubricant and an organic solvent selected as to be the most suitable ones with respect to the intended form of administration.

In the preferred embodiment of the present invention, the binder may include, but is not limited to hydroxypropyl cellulose, cellulose or cellulose derivatives, povidone, starch or mixtures thereof. Preferably, the binder is hydroxypropyl cellulose.

In the preferred embodiment of the present invention, the antioxidant may include, but is not limited to butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, sodium sulfite, sodium thiosulfate, monothioglycerol, tert-butyl hydroquinone, ethoxyquin, dithiothreitol, and derivatives thereof. Preferably, the antioxidant is butylated hydroxy toluene.

In the preferred embodiment of the present invention, the lubricant may include, but is not limited to magnesium stearate, zinc stearate, calcium stearate, talc, carnauba wax, stearic acid, sodium stearyl fumarate sodium laurel sulfate, glyceryl palmitostearate, and hydrogenated vegetable oils and fats, as well as other known lubricants. Preferably, the lubricant is magnesium stearate.

The embodiment in accordance with the present invention was designed with adjusted quantitative composition composed of pharmaceutically acceptable ingredients mentioned above by using wet granulation process.

The embodiment identified as Example 1 was given in the Table 1 below.

The proposed embodiment based on the invention provided a prolonged release solid pharmaceutical composition is as stated below:

Table 1: Unit formula of Example 1 The detailed manufacturing steps of Example 1 presented prolonged release behaviour were presented below: i. Mirabegron, polyethylene oxide, hydroxypropyl methylcellulose and hydroxypropyl cellulose were screened through a proper sieve and transferred into cubic mixer and stirred, ii. Butylated hydroxytoluene was dissolved in sufficient quantity of an organic solvent and added to the preparation in Step (i) to perform granulation process, iii. The granules prepared in Step (ii) were dried in high-shear mixer and shifted through a proper sieve, iv. Magnesium stearate was screened through a proper sieve and added to the granules prepared in Step (iii) and stirred to obtain a uniform final blend, v. Tablet compression was performed with the final blend in Step (iv).

Compressed tablets were subjected to in vitro dissolution study. The conditions of dissolution study are set by US&FDA, based on the information the main dissolution medium is phosphate buffer, pH 6.8. Other conditions are defined as; volume of dissolution medium is 900 ml, temperature of study is 37°C±0.5, rotation speed is 100 rpm, apparatus is basket and the duration of dissolution study is 12 hours.

The amount of dissolved active ingredient over time was determined by HPLC.

Table 2: Comparative dissolution profile for Example 1 in pH 6.8 phosphate buffer

Based on the results presented in Table 2 above, the release pattern of Example 1 was remarkably slower than the reference drug product.

According to The Guideline on the Investigation of Bioequivalence, the in vitro dissolution profile of two drug products is evaluated based on the value of similarity factor f2, if that value is higher than 50, the two drug products in comparison show similar dissolution profiles. The similarity factor f2 of Example 1 and the reference drug product was calculated as 29.4 since this value was below 50 the products compared were not similar.

Thus, another example was proposed to obtain proper in vitro dissolution characteristics by doing the modifications given in the Table 3 below.

Table 3: The amount ranges of the hydrogel forming agents between Example 1 and Example 2

Other ingredients were also adjusted within the given range in Table 1. The manufacturing process was the same with the Example 1.

After getting final blend of Example 2, the next step was considered as tablet compression. However, the flowability of final blend was not suitable for the compression. Then, it is not processed.

Thus, another example was proposed to obtain proper final blend with exhibiting similar in vitro dissolution profile to reference drug product by redesigning the formulation stated below.

The amount of hydrogel forming agents in the total tablet weight was decreased to use suitable amount of suitable tableting agents such as diluent and glidant that improve final blend properties. o Microcrystalline cellulose was pharmaceutical excipient used as diluent, o Colloidal silicon dioxide was pharmaceutical excipient used as glidant.

Diluents are fillers which are frequently used to increase the bulk weight of a tablet or capsule to provide sufficient mass and volume.

Microcrystalline cellulose is one of the most frequent used types of filler in the pharmaceutical formulations because its porosity enhances liquid uptake, thus making swelling of the drug product is faster and easier. Due to this property, in the preferred embodiment of the present invention microcrystalline cellulose was selected as an excipient having good binding properties for wet granulation to promote rapid wetting of hydrogel forming agents. Glidants are used in the pharmaceutical composition to enhance product flow by reducing interparticulate friction.

Colloidal silicon dioxide is one of the types of glidant in tableting processes and encapsulation for promoting the flowability of the granulation. Due to this properties, in the preferred embodiment of the present invention colloidal silicon dioxide was selected as an excipient to obtain proper final blend of the matrix core tablet.

Table 4: The amount range of the hydrogel forming agents in Example 3

The mixture of polyethylene oxide and hydroxypropyl methylcellulose is in a ratio of 4:3.

The formulation of proposed embodiment identified as Example 3 is given in the Table 5. Table 5: Unit formula of Example 3

The detailed manufacturing steps of Example 3 presenting prolonged release of mirabegron were presented below: i. Mirabegron and polyethylene oxide were screened through a proper sieve and transferred into cubic mixer and stirred, ii. Microcrystalline cellulose, hydroxypropyl methylcellulose and hydroxypropyl cellulose were screened through a proper sieve and added to the preparation in Step (i) to perform granulation process, iii. Butylated hydroxytoluene was dissolved in sufficient quantity of an organic solvent and added to the preparation in Step (ii) to perform granulation process, iv. The granules prepared in Step (iii) were dried in high-shear mixer and shifted through a proper sieve, v. Magnesium stearate was screened through a proper sieve and added to the granules prepared in Step (iv), vi. Colloidal silicon dioxide was screened through a proper sieve and added to the granules prepared in Step (v) and stirred to obtain a uniform final blend.

After getting final blend of Example 3, the compression process was performed. Then, compressed tablets were subjected to in vitro dissolution study within the conditions stated above and the comparative results are presented in Table 6.

Table 6: Comparative dissolution profiles for Example 3 in pH 6.8 phosphate buffer

Based on the results presented in Table 6 above, the release pattern of Example 3 was similar to the reference drug product, in which the similarity factor f2 was calculated as 62.1.

The proper dissolution profile of the tablet formulation obtained by using dedicated amounts of diluent and glidant was obtained when the amount ratio of the hydrogel forming agents as 4:3.

In the present invention, a pharmaceutical composition comprising mirabegron and at least one pharmaceutical composition was provided in prolonged release wherein more than 85% of mirabegron was release in 8.5 hour in pH 6.8 phosphate buffer solution simulated the small intestinal (SI) environment.

However, after oral administration of drug comprising mirabegron is confronted with different environments at the gastrointestinal tract until reach its targeted tissue in the small intestinal. According to pharmacokinetic results of mirabegron, the absorption of mirabegron from the stomach is 7%, but contrary to this, in the duodenum, jejunum and colon its absorption is estimated as 56%, 62% and 15%, respectively. Thus, it is crucial also to take into account the stomach and proximal colon during designing a pharmaceutical composition.

Besides that, to understand oral bioavailability in the development of prolonged release dosage oral dosage forms, in vitro-in vivo correlation is investigated wherein in vitro dissolution helps the interpretation of the modified release dosage form with food effects on bioavailability. Thus, the different dissolution medium used were 0. IN HC1 having pH 1.2, the acetate buffer solution of pH 4.5.

In the preferred embodiment of present invention, the developed final Example 3 was subjected also to in vitro dissolution study at 0.1N HC1 to stimulate the gastric conditions and at pH 4.5 to stimulate the proximal colon. The rest of other conditions of dissolution study were kept same.

Table 7: Comparative dissolution profiles for Example 3 in 0. IN HC1 and pH 4.5 acetate buffer

Based on the results presented in Table 7 above, the release patterns of Example 3 in 0.1N HC1 and pH 4.5 acetate buffer were remarkably faster than the reference drug product.

The similarity factor f2 of Example 3 was calculated as 33.2 for 0.1N HCI and 37.6 for pH 4.5 acetate buffer.

To obtain proper dissolution profiles of mirabegron in 0.1N HCI, pH 4.5 and pH 6.8 buffer solutions, another example was proposed.

In the preferred embodiment, the amount of hydroxypropyl cellulose was increased from the range of 1.0% - 4.0% to 5.0% to 10% by weight of the total core tablet, in order to achieve better control and regulate the drug release to improve dissolution profile to be more similar to reference drug product. The preferred embodiment identified as Example 4 was given in the Table 8 below.

Table 8: Unit formula of Example 4

After getting final blend of Example 4, the compression process was performed. Then, compressed tablets were subjected to in vitro dissolution studies in 0.1N HC1, pH 4.5, pH 6.8 buffer solutions. The rest of other conditions of dissolution study were kept same.

Table 8: Comparative dissolution profiles for Example 4 in 0.1N HC1, pH 4.5 acetate buffer and pH 6.8 phosphate buffer

Based on the results presented in Table 8 above, the release patterns of Example 4 in 0. IN HC1, pH 4.5 acetate buffer and pH 6.8 phosphate buffer were similar to the reference drug product, in which the similarity factor f2 were calculated for all buffer solutions as 61.9, 66.9 and 68.3 respectively.

According to the results presented above, the dissolution profile of mirabegron in a prolonged release composition comprising at least two hydrogel forming agents and binder with other pharmaceutically acceptable excipients is more than 85% in 8.5 h in GI dissolution media (0.1N HC1, pH 4.5, pH 6.8 buffer solutions at 37±0.5°C) wherein polyethylene oxide was used as hydrogel forming agent having an average molecular weight of approximately 2,000,000 or a viscosity of 2000 to 4000 cP at a 2% aqueous solution at 25°C, hydroxypropyl methylcellulose is used as hydrogel forming agent having a viscosity within the range of 80 to 120 cP in 2% aqueous water at 20°C, the amount ratio of polyethylene oxide and hydroxypropyl methylcellulose is 4:3, the amount of hydroxypropyl cellulose used as binder was between 5% - 10% wt by the total weight of the composition,

While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.

Claims

1. A pharmaceutical composition comprising mirabegron or a pharmaceutically acceptable salt thereof, at least two hydrogel forming agents, a binder and at least one pharmaceutically acceptable excipient, wherein

• One of the hydrogel forming agents has an average molecular weight of approximately 2,000,000 or a viscosity of 2000 to 4000 cP at a 2% aqueous solution at 25° C,

• Other hydrogel forming agent has a viscosity within the range of 80 to 120 cP in 2% aqueous water at 20° C,

• the amount ratio between the hydrogel forming agents is 4:3,

• the amount of binder is in the range of 5% - 10% w/w by the weight of the total composition, wherein more than 85% of mirabegron is released after 8.5 h in 0. IN HC1, pH 4.5, pH 6.8 buffer solutions at temperature of 37±0.5°C using USP type I (basket) apparatus rotating at 100 rpm and the pharmaceutical composition is polyethylene glycol-free.

2. A pharmaceutical composition according to claim 1, wherein the mirabegron is in a free form.

3. A pharmaceutical composition according to any one of the preceding claims, wherein the composition is in a prolonged release dosage form.

4. A pharmaceutical composition according to any one of the preceding claims, wherein at least two hydrogel forming agents are selected from polyethylene, polyethylene oxide, ethyl cellulose, hydroxypropyl methylcellulose and hydroxypropyl cellulose and their copolymers.

5. A pharmaceutical composition according to any one of the preceding claims, wherein one of the hydrogel forming agent is polyethylene oxide.

6. A pharmaceutical composition according to any one of the preceding claims, wherein the other hydrogel forming agent is hydroxypropyl methylcellulose.

7. A pharmaceutical composition according to any one of the preceding claims, wherein the binder is selected from hydroxypropyl cellulose, cellulose or cellulose derivatives, povidone, starch, sucrose, polyethylene glycol, or mixtures thereof. A pharmaceutical composition according to Claim 7, wherein the binder is hydroxypropyl cellulose. A pharmaceutical composition according to any one of the preceding claims, wherein at least one pharmaceutically acceptable excipient is selected from antioxidants, lubricants, organic solvents and mixtures thereof. A pharmaceutical composition according to any one of the preceding claims, wherein the composition is prepared by using wet granulation method. A pharmaceutical composition according to any one of the preceding claims for use in the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency.