DESC:FIELD OF THE INVENTION
The present invention relates to an extended release pharmaceutical composition of mirabegron and process for its preparation.

BACKGROUND OF THE INVENTION
Mirabegron is a selective agonist for human beta 3-adrenoceptor (beta 3-AR) which is dominant in the human detrusor muscle. Activation of beta-AR in the bladder trigone facilitates urine storage through flattening and lengthening of the bladder base. It has following chemical structure.

It is approved as for the symptomatic treatment of urgency, increased micturition frequency and/or urgency incontinence as may occur in patients with overactive bladder (OAB) syndrome. In Europe, it is available as Betmiga® 25 mg and 50 mg prolonged-release tablets. The drug product is formulated as prolonged release film coated tablets. The tablets are formulated as a hydrophilic gel-forming matrix tablet formulation, designed for continuous drug release throughout the GI tract. The dose is 50 mg once daily with or without food. In patients with severe renal impairment or with moderate hepatic impairment, the recommended dose of mirabegron is 25 mg orally once daily with or without food.

The US patent no. 6,346,532 discloses mirabegron.
The US patent no. 7,342,117 discloses crystalline forms of mirabegron.
The US patent no. 8,835,474 discloses use of mirabegron as a remedy for use in the treatment of overactive bladder.

It is known in the art that mirabegron in the form of conventional formulations revealed disadvantages, for example, that pharmacokinetic data unexpectedly varied according to the presence or absence of the intake of food. For example, the rate of decrease of Cmax in a fed state was 67%, and the rate of decrease of AUC in the fed state was 47%, in comparison with those in a fasted state. These problems are considered to be raised by, for example, the changes in pharmacokinetics caused by food, and therefore, the development of a formulation capable of avoiding the effects by food intake is desired.

EP2345410B1 patent discloses a pharmaceutical composition for modified release, comprising (1) mirabegron (2) at least one additive which ensures penetration of water into the pharmaceutical composition and which has a solubility such that the volume of water required for dissolving 1 g of the additive is 10 mL or less, and (3) a hydrogel-forming polymer having an average molecular weight of 1,00,000 to 50,00,000 or a viscosity of 12 mPa•s or more in a 5% aqueous solution at 25°C and 7,500 mPa•s or less in a 1% aqueous solution at 25°C, wherein the hydrogel-forming polymer is compound selected from the group consisting of polyethylene oxide, hydroxypropyl methylcellulose, and hydroxypropyl cellulose.

Therefore, in view of the above problems, there is the need for compositions of Mirabegron which are simple, easy to manufacture and provide for an extended release of Mirabegron.

SUMMARY OF THE INVENTION
The present invention relates to an extended release pharmaceutical composition of mirabegron comprising mirabegron or a pharmaceutically acceptable salt thereof, polyethylene glycol having an average molecular weight of 1,800 to 9,000 and polyethylene oxide having an average molecular weight of 70,00,000 to 1,00,00,000 and a viscosity of more than 7,500 mPa•s in a 1% aqueous solution at 25 °C.

In one embodiment the present invention relates to an extended release pharmaceutical composition of mirabegron comprising mirabegron or a pharmaceutically acceptable salt thereof, polyethylene glycol having an average molecular weight of 1,800 to 9,000, polyethylene oxide having an average molecular weight of 70,00,000 to 1,00,00,000 and a viscosity of more than 7,500 mPa•s in a 1% aqueous solution at 25 °C and at least one pharmaceutical acceptable excipient.

The present invention further relates to a process for the preparation of an extended pharmaceutical composition of mirabegron.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an extended release pharmaceutical composition of mirabegron comprising mirabegron or a pharmaceutically acceptable salt thereof, polyethylene glycol having an average molecular weight of 1,800 to 9,000 and polyethylene oxide having an average molecular weight of 70,00,000 to 100,00,000 and a viscosity of more than 7,500 mPa•s in a 1% aqueous solution at 25 °C.

In one embodiment the present invention relates to an extended release pharmaceutical composition of mirabegron comprising mirabegron or a pharmaceutically acceptable salt thereof, polyethylene glycol having an average molecular weight of 1,800 to 9,000, polyethylene oxide having an average molecular weight of 70,00,000 to 1,00,00,000 and a viscosity of more than 7,500 mPa•s in a 1% aqueous solution at 25 °C and at least one pharmaceutical acceptable excipient.

In another embodiment the present invention relates to an extended release pharmaceutical composition of mirabegron comprising mirabegron or a pharmaceutically acceptable salt thereof, polyethylene glycol having an average molecular weight of 1,800 to 9,000, polyethylene oxide having an average molecular weight of 70,00,000 and a viscosity between 7,500 and 10,000 mPa•s in a 1% aqueous solution at 25 °C and at least one pharmaceutical acceptable excipient.

In yet another embodiment the present invention relates to an extended release pharmaceutical composition of mirabegron comprising mirabegron or a pharmaceutically acceptable salt thereof, polyethylene glycol having an average molecular weight of 1,800 to 9,000, polyethylene oxide having an average molecular weight of 80,00,000 and a viscosity between 10,000 and 15,000 mPa•s in a 1% aqueous solution at 25 °C and at least one pharmaceutical acceptable excipient.

In another embodiment the present invention relates to an extended release pharmaceutical composition of mirabegron comprising mirabegron or a pharmaceutically acceptable salt thereof, polyethylene glycol having an average molecular weight of 1,800 to 9,000, polyethylene oxide having an average molecular weight of 75,00,000 and a viscosity between 7,500 and 13,000 mPa•s in a 1% aqueous solution at 25 °C and at least one pharmaceutical acceptable excipient.

In another embodiment the present invention relates to an extended release pharmaceutical composition of mirabegron comprising mirabegron or a pharmaceutically acceptable salt thereof, polyethylene glycol having an average molecular weight of 1,800 to 9,000, polyethylene oxide having an average molecular weight of 85,00,000 and a viscosity of more than 13,000 mPa•s in a 1% aqueous solution at 25 °C and at least one pharmaceutical acceptable excipient.

In some embodiments, the composition of the present invention has an in vitro release profile of Mirabegron which is similar or identical to that of Betmiga®. Such a similar in vitro release profile is normally a good indication that the resulting product will be bioequivalent to Betmiga®.

In another embodiment the present invention relates to an extended release pharmaceutical composition of mirabegron wherein the composition is stable under storage conditions of 25°C/60% RH, 30°C/65% RH, and/or 40°C/75% RH.

Mirabegron may be present in an amount of 1 to 50% w/w, preferably 5 to 30% w/w, more preferably 10 to 20% w/w of the total composition.

Polyethylene glycol (PEG) having an average molecular weight of 1,800 to 9,000 may be selected from PEG 2000, PEG 3000, PEG 3350, PEG 4000, PEG 4600 or PEG 8000. PEG may be present in an amount of 20 to 90 % w/w, preferably 40 to 80 % w/w, more preferably 50 to 80 % w/w of the total composition.

Polyethylene oxide may be present in an amount of 1 to 80% w/w, preferably 5 to 50% w/w, preferably 8 to 40% w/w, more preferably 10 to 20% w/w of the total composition. Polyethylene oxide having an average molecular weight of 70,00,000 and a viscosity between 7,500 and 10,000 mPa•s in a 1% aqueous solution at 25 °C is commercially available as PEO -20 NF.

The pharmaceutical acceptable excipient includes but not limited to one or more of binder, antioxidant, lubricant, diluent, glidant disintegrant, plasticizer, anticaking agent, film coating agent and coloring agent.

Binder includes but not limited to hydroxypropyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxymethyl cellulose, copovidone and mixtures thereof. Binder may be present in an amount of 0.1 to 10% w/w of the total composition.

Antioxidant include butylated hydroxytoluene (BHT), butylhydroxyanisol (BHA), ascorbic acid, sodium ascorbate, propyl gallate (PG), erythorbic acid, sodium nitrite, sodium bisulfite, sodium pyrosulfite, citric acid, edetate sodium and mixtures thereof. Antioxidant may be present in an amount of 0.001 to 1% w/w of the total composition.

Diluent includes but not limited to calcium hydrogen Phosphate, lactose, dextrose, sucrose, maltose, mannitol, microcrystalline cellulose and mixtures thereof. Diluent may be present in an amount of 0 to 50% w/w of the total composition.

Disintegrant includes but not limited to corn starch, potato starch, croscarmellose sodium, crospovidone, sodium starch glycolate and mixtures thereof. Disintegrant may be present in an amount of 0 to 10% w/w of the total composition.

A glidant is an excipient that improves the flow characteristics of a compressible powder such as tablet ingredients or granules. Two of the most common glidants are colloidal silicon dioxide (CAB-O-SIL®) and hydrated silicon Dioxide (SYLOID 244 FP). Glidant may be present in an amount of 0 to 5% w/w of the total composition.

Lubricant includes but not limited to magnesium stearate, talc, stearic acid, glyceryl monostearate, sodium stearyl fumarate, glyceryl behenate, hydrogenated oils, polyethylene glycols and sodium stearate. Lubricant may be present in an amount of 0.1 to 5% w/w of the total composition.

Film coating agent and coloring agent may be used in the present invention are commercially available from Colorcon under the trade name OPADRY®, such as Opadry® clear, Opadry® white, Opadry orange or Opadry ® yellow.

Plasticizer includes but not limited to triethyl citrate, acetyltributyl citrate, triacetin, acetylated monoglyceride, olive oil, sesame oil, acetyltriethyl citrate, glycerin sorbitol, diethyloxalate, diethylmalate, diethylfumarate, dibutylsuccinate, diethylmalonate, dioctylphthalate, dibutylphthalate, dibutylsebacate, tributylcitrate, glyceroltributyrate, polyethylene glycol, propylene glycol and mixtures thereof. Plasticizer may be present in an amount of 0 to 5% w/w of the total composition.

The pharmaceutical composition according to the invention is solid dosage form selected from tablets, granules or capsules. The granules may be filed into sachets.

The extended release pharmaceutical composition of mirabegron of the present invention may be prepared by mixing the mirabegron with Polyethylene glycol, Polyethylene oxide and optionally conventional processing aids, such as binder, diluent, disintegrant, glidant, lubricant, or mixtures thereof. The mixture may be directly compressed into a tablet or mini tablet or granulated, either by wet or dry techniques to prepare pellets. Alternatively, the mixture may be compressed to form slugs followed by milling to form granules. The granules may also be used to prepare compressed tablet or mini tablet. Alternatively, the granules or mini tablet may be filled into the capsules.

In the preparation of the tablets according to the invention, various conventional, well-known solvents may be used to prepare the tablets and optionally apply a film coating to the tablets.

The dissolution profile of the extended release composition of mirabegron of the present invention was tested in a USP type I (Basket) apparatus at 100 rpm in 900 ml Phosphate Buffer pH 6.8. The drug dissolution rate from the extended release composition of mirabegron of the present invention is not more than 20% in one hour, between 30 % to 70% in 5 hours and not less than 80% in 12 hours.

Examples
Example 1
Table 1: Extended release tablets of mirabegron
Ingredients mg/ Unit
(25 mg) mg/ Unit
(50 mg)
SLUGGING
Mirabegron 25.00 50.00
Polyethylene Glycol 8000
(Macrogol 8,000) Carbowax Sentry 182.60 157.60
Polyethylene Oxide (PEO -20 NF) 32.00 32.00
Hydroxypropyl cellulose (Klucel EXF Pharm) 7.50 7.50
Butylated Hydroxy Toulene 0.40 0.40
INTRA GRANULAR LUBRICATION
Magnesium stearate 1.25 1.25
Weight of Granular Blend 247.50 247.50
EXTRA GRANULAR LUBRICATION
Magnesium stearate 1.25 1.25
Target Weight of Core Tablet 250.00 250.00
FILM COATING
Hypromellose (6 cps) 5.25 5.25
Polyethylene Glycol 6000 1.50 1.50
Iron oxide yellow NA 0.25
Sunset yellow lake 0.25 NA
Purified Water Qs Qs
Total Weight of Tablets 257.00 257.00

Method of preparation:
Mirabegron, Polyethylene glycol 8000, Polyethylene oxide (PEO-20 NF), Klucel EXF and Butylated Hydroxy toulene were co-sifted through #25 S.S. sieve fitted to a Vibratory sifter. This mixture was transferred to blender and blended for 10 minutes at 10 RPM. Magnesium stearate was sifted through ASTM # 60 SS sieve and mixed with the above blend. The lubricated material was compressed to form slugs. The slugs milled to form granules and passed through ASTM #25 S.S. The granules were lubricated with magnesium stearate in a blender for 3 min at 10 RPM and compressed into tablets. The compressed tablets were coated with a film coating solution.

Example 2
Dissolution study
Mirabegron ER Tablets 50 mg of example 1 exhibited following dissolution profile when tested using USP Type I (Basket) apparatus at 100 rpm in 900 ml Phosphate Buffer pH 6.8.
Table 2: Dissolution study of Mirabegron ER Tablets 50 mg of example 1
Time points % Drug release
1 hour 9.9
3 hours 26.0
5 hours 45.4
7 hours 67.5
8.5 hours 81.0
10 hours 92.8
12 hours 100.0

Example 3
Stability study
Mirabegron ER Tablets 50 mg of example 1 were blister packed and stored under the conditions at 40°C and 75% RH. Then the tablets were subjected to a dissolution test according to example 2. The results are provided in the following Table 3.
Table 3: Dissolution study of Mirabegron ER Tablets 50 mg of example 1 stored at 40°C and 75% RH
Time points % Drug release
Initial 1 Month 2 Month
1 hour 9.9 14.1 15.5
5 hours 45.4 65.2 64.8
12 hours 100.0 99.2 100.1
,CLAIMS:1. An extended release pharmaceutical composition of mirabegron comprising mirabegron or a pharmaceutically acceptable salt thereof,
polyethylene glycol having an average molecular weight of 1,800 to 9,000,
polyethylene oxide having an average molecular weight of 70,00,000 to 1,00,00,000 and a viscosity of more than 7,500 mPa•s in a 1% aqueous solution at 25 °C, and
at least one pharmaceutically acceptable excipient.
2. The pharmaceutical composition according to claim 1 wherein the polyethylene oxide has an average molecular weight of 70,00,000 and a viscosity between 7,500 and 10,000 mPa•s in a 1% aqueous solution at 25 °C.
3. The pharmaceutical composition according to claim 1 wherein Mirabegron is present in an amount of 1 to 50% w/w based on final weight of the composition.
4. The pharmaceutical composition according to claim 1 wherein Polyethylene glycol is present in an amount of 20 to 90 % w/w based on final weight of the composition.
5. The pharmaceutical composition according to claim 1 wherein Polyethylene oxide is present in an amount of 1 to 80% w/w based on final weight of the composition.
6. The pharmaceutical composition according to claim 1 wherein the composition exhibited dissolution profile of more than 20% in one hour, between 30 % to 70% in 5 hours and not less than 80% in 10 hours when tested in a USP type I (Basket) apparatus at 100 rpm in 900 ml Phosphate Buffer pH 6.8.
7. The pharmaceutical composition according to claim 1 wherein the pharmaceutically acceptable excipient is selected from one or more of binder, antioxidant, lubricant, diluent, glidant disintegrant, plasticizer, anticaking agent, film coating agent and coloring agent.
8. The pharmaceutical composition according to claim 7 wherein the binder is hydroxypropyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxymethyl cellulose, copovidone or mixture thereof.
9. The pharmaceutical composition according to claim 7 wherein the antioxidant is butylated hydroxytoluene (BHT), butylhydroxyanisol (BHA), ascorbic acid, sodium ascorbate, propyl gallate (PG), erythorbic acid, sodium nitrite, sodium bisulfite, sodium pyrosulfite, citric acid, edetate sodium or mixture thereof.
10. The pharmaceutical composition according to claim 1 wherein the composition is solid dosage form selected from tablet, granule or capsule.