DESC:FIELD OF THE INVENTION
The present invention refers to a controlled release pharmaceutical composition of mirabegron.

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.

In this context, the US patent no. 10,842,780 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 100,000 to 5,000,000 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.
Therefore, in view of the above problems, there is the need for compositions of Mirabegron which are simple, easy to manufacture and provide for a controlled release of Mirabegron.

SUMMARY OF THE INVENTION
The present invention relates to a controlled release pharmaceutical composition of mirabegron comprising mirabegron or a pharmaceutically acceptable salt thereof and a non hydrogel-forming excipient.

In one embodiment the present invention relates to a controlled release pharmaceutical composition of mirabegron comprising mirabegron or a pharmaceutically acceptable salt thereof and a non hydrogel-forming excipient selected from glycerol dibehenate, ethyl cellulose, cellulose acetate, amino methacrylate copolymer or methacrylate copolymer and at least one pharmaceutical acceptable excipient.

In another embodiment the present invention relates a controlled release pharmaceutical composition of mirabegron comprising a) a core comprising mirabegron or a pharmaceutically acceptable salt thereof and a non hydrogel-forming excipient selected from glycerol dibehenate, ethyl cellulose, cellulose acetate or mixtures thereof and b) a coating layer comprising a polymer selected from ethyl cellulose, cellulose acetate, amino methacrylate copolymer, methacrylate copolymer or mixtures thereof.
The present invention further relates to a process for the preparation of controlled release pharmaceutical composition of mirabegron.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a controlled release pharmaceutical composition of mirabegron comprising mirabegron or a pharmaceutically acceptable salt thereof and a non hydrogel-forming excipient.

In one embodiment the present invention relates to a controlled release pharmaceutical composition of mirabegron comprising mirabegron or a pharmaceutically acceptable salt thereof and a non hydrogel-forming excipient selected from glycerol dibehenate, ethyl cellulose, cellulose acetate, amino methacrylate copolymer or methacrylate copolymer and at least one pharmaceutical acceptable excipient.

In another embodiment the present invention relates a controlled release pharmaceutical composition of mirabegron comprising a) a core comprising mirabegron or a pharmaceutically acceptable salt thereof and a non hydrogel-forming excipient selected from glycerol dibehenate, ethyl cellulose, cellulose acetate or mixtures thereof and b) a coating layer comprising a polymer selected from ethyl cellulose, cellulose acetate, amino methacrylate copolymer, methacrylate copolymer or mixtures thereof.

The core may be in the form of pellets, mini tablets or tablets. As used herein the term “pellets” refer to spherical or irregularly shaped particles having an average diameter of less than 1 mm. As used herein the terms “mini tablet” refer to solid dosage forms that have a length and/or width that ranges from 1 mm or greater to about 5 mm. As used herein the term “tablet” is used in its conventional manner, and generally refers to a solid dosage form with a length and/or width greater than 5 mm. In the case of mini tablets and tablets the core is preferably a homogenous or uniform mixture of ingredients, i.e., not a multilayer core. The core may further comprise conventional tableting excipients such as binder, diluent, disintegrant, glidant, lubricant or mixtures thereof.

The coating layer is applied to and surrounds the core. In one embodiment of the present invention, the dosage forms employs only one functional coating layer and may optionally further comprise film coating. The coating layer, also referred to herein as a “functional coating,” may further comprise conventional processing aids such as binder, filler, pigment, lubricant, plasticizer and mixtures thereof.

In some embodiments, the coating layer comprises a polymer which is insoluble in water but soluble in aqueous media with a pH below 5.

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®.

Mirabegron may be present in an amount of 1 to 50% w/w of the total composition.

The polymer for example amino methacrylate copolymer is Eudragit® RS, Eudragit® RL PO.

The polymer for example methacrylate copolymer is Eudragit L. Additional examples are Eudragit ® E 100, Eudragit ® E PO and Eudragit ® 12.5.

The non hydrogel-forming excipient may be present in an amount of 10 to 80% w/w of the total composition.

Polymer may be present in an amount of 10 to 80% w/w of the total composition.

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

Binder includes but not limited to polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, copovidone and mixtures thereof. Binder may be present in an amount of 0 to 10% 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 20 to 80% 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 0.1 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 0.01 to 5% w/w of the total composition.

The controlled release pharmaceutical composition of mirabegron of the present invention may be prepared by mixing the mirabegron with a non hydrogel-forming excipient, 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. The granules may also be used to prepare compressed tablet or mini tablet.

In the preparation of the tablets according to the invention, various conventional, well-known solvents may be used to prepare the tablets and apply the functional coating to the tablets.
The controlled release pharmaceutical composition of mirabegron of the present invention may be in the form of tablets or capsules.

The dissolution profile of the controlled release composition of mirabegron of the present invention was tested in a USP type 1 (Basket) apparatus at 100 rpms in 900 ml of a Acetate buffer of 3.5 pH at a temperature of about 37 °C ± 0.5 °C.

In one embodiment the controlled release composition of mirabegron of the present invention exhibited dissolution profile of more than 20% in one hour, between 30 % to 75% in 5 hours and not less than 80% in 10 hours when tested in a USP type 1 (Basket) apparatus at 100 rpms in 900 ml of a Acetate buffer of 3.5 pH at a temperature of about 37 °C ± 0.5 °C.

Examples
Example 1
Controlled release tablets of mirabegron
Ingredients mg/ Unit
(25 mg) mg/ Unit
(50 mg)
SLUGGING
Mirabegron 25.00 50.00
Glycerol dibehenate 87.50 87.50
Calcium hydrogen phosphate dihydrate 25.00 25.0
Lactose monohydrate
(Spray dried, Super Tab 30 GR) 95.10 70.1
SYLOID 244 FP
(Hydrated silicon Dioxide) 6.20 6.20
Purified Talc 6.20 6.20
INRA GRANULAR LUBRICATION
Magnesium stearate 2.50 2.50
Weight of Granular Blend 247.50 247.50
EXTRA GRANULAR LUBRICATION
Magnesium stearate 2.50 2.50
Target Weight of Core Tablet 250.00 250.00
SUSTAINED RELEASED COATING
Eudragit ® RL PO (Ammonio methacrylate copolymer, Type A) 11.25 11.25
Triethyl Citrate 1.13 1.13
Purified Talc 5.63 5.63
TOTAL WEIGHT OF SR COATED TABLETS 268.00 268.00

Mirabegron and glycerol dibehenate were co-sifted through #30 S.S. sieve fitted to a Vibratory sifter. This mixture was transferred to blender and blended for 30 minutes at fast RPM. Lactose monohydrate (Spray dried, Super Tab 30 GR) and calcium hydrogen phosphate dihydrate were co-sifted through #30 S.S. sieve fitted to a Vibratory sifter and blended with the above blend for 10 min. Purified Talc and SYLOID 244 FP were co-sifted through #30 S.S. sieve fitted to a Vibratory sifter and blended with the above blend for 10 min. 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. The granules were lubricated with magnesium stearate in a blender for 3 min and compressed into tablets. Acetone, isopropyl alcohol and purified water were mixed to form a solvent mixture. Eudragit RL PO was dispersed in 50% of the solvent mixture to form a first solution. Triethyl Citrate was separately dispersed in 50% of the solvent mixture followed by addition of purified Talc to form a second solution. The two solutions were mixed to form a coating solution. The compressed tablets were loaded in auto –coater and coated with the coating solution to form the coated tablets.

Example 2
The controlled release composition of mirabegron of example 1 exhibited following dissolution profile when tested using USP type 1 (Basket) apparatus at 100 rpm in 900 ml of a Acetate buffer solution of 3.5 pH at a temperature of about 37 °C ± 0.5 °C.
Time points Betmiga 50 mg
prolonged-release tablets
(Reference Product) Mirabegron ER Tablets 50 mg
(Test Product)
% Drug release
1Hr 17.8 25.8
3 Hrs 48.2 54.4
5 Hrs 75.1 71.7
7 Hrs 95.3 82.7
8.5 Hrs 100.7 90.5
10 Hrs 103.1 96.2
12 Hrs 103.2 99.7
F2 54.95

Example 3
Controlled release tablets of mirabegron

Ingredients mg/Tablets % w/w
Mirabegron 50.00 25.0
Lactose (Super Tab 30 GR) 98.00 49.0
MCC PH 102 45.00 22.5
Talc 4.00 2.0
Mg Stearate 3.00 1.5
Weight of core Tablets 200.00 100.0
SR Coating
Surelease* 5.0 2.50%
Purified water q.s. -
Weight of SR Coating 205.0 -
* Surelease contains oleic acid, ethylcellulose, medium chain triglycerides.

Mirabegron, Lactose (Super Tab 30 GR), MCC PH 102, Purified Talc were co-sifted through #30 S.S. sieve fitted to a Vibratory sifter. This mixture was transferred to blender and blended for 20 minutes at fast RPM. Magnesium stearate was sifted through ASTM # 60 SS sieve and mixed with the above blend. The granules were lubricated with magnesium stearate in a blender for 3 min and compressed into tablets. Surelease was dispersed in purified water to form a coating dispersion. The compressed tablets were loaded in auto –coater and coated with the coating solution to form the coated tablets.

Example 4
Controlled release tablets of mirabegron
Ingredients mg/Tablets % w/w
Mirabegron 50.00 20.0
Glycerol Dibehenate 100.0 40.0
Calcium hydrogen Phosphate Dihydrate 25.0 10.0
Lactose (Super Tab 30 GR) 73.0 29.2
Magnesium stearate 2.0 0.8
Weight of Tablets 250.0 100.0

Mirabegron and glycerol dibehenate were co-sifted through #30 S.S. sieve fitted to a Vibratory sifter. This mixture was transferred to blender and blended for 30 minutes at fast RPM. Lactose monohydrate (Spray dried, Super Tab 30 GR) and calcium hydrogen phosphate dihydrate were co-sifted through #30 S.S. sieve fitted to a Vibratory sifter and blended with the above blend for 10 min. 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. The granules were lubricated with magnesium stearate in a blender for 3 min and compressed into tablets.

CLAIMS:

1. A controlled release pharmaceutical composition of mirabegron comprising mirabegron or a pharmaceutically acceptable salt thereof and a non hydrogel-forming excipient selected from glycerol dibehenate, ethyl cellulose, cellulose acetate, amino methacrylate copolymer or methacrylate copolymer and at least one pharmaceutical acceptable excipient.

2. A controlled release pharmaceutical composition of mirabegron comprising a) a core comprising mirabegron or a pharmaceutically acceptable salt thereof and a non hydrogel-forming excipient selected from glycerol dibehenate, ethyl cellulose, cellulose acetate or mixtures thereof and b) a coating layer comprising a polymer selected from ethyl cellulose, cellulose acetate, amino methacrylate copolymer, methacrylate copolymer or mixtures thereof.

3. The pharmaceutical composition of mirabegron as claimed in claim 2 wherein the core is in the form of pellets, mini tablets or tablets.

4. The pharmaceutical composition of mirabegron as claimed in claim 2 wherein the core further comprise conventional tableting excipients such as binder, diluent, disintegrant, glidant, lubricant or mixtures thereof.

5. The pharmaceutical composition of mirabegron as claimed in claim 2 wherein the coating layer further comprise conventional processing aids such as binder, filler, pigment, lubricant, plasticizer and mixtures thereof.

6. The pharmaceutical composition of mirabegron as claimed in claim 2 wherein the coating layer comprises a polymer which is insoluble in water but soluble in aqueous media with a pH below 5.

7. The pharmaceutical composition of mirabegron as claimed in claim 2 wherein Mirabegron is present in an amount of 1 to 50% w/w of the total composition.

8. The pharmaceutical composition of mirabegron as claimed in claim 2 wherein the composition exhibited dissolution profile of more than 20% in one hour, between 30 % to 75% in 5 hours and not less than 80% in 10 hours when tested in a USP type 1 (Basket) apparatus at 100 rpms in 900 ml of a Acetate buffer of 3.5 pH at a temperature of about 37 °C ± 0.5 °C.

9. The pharmaceutical composition of mirabegron as claimed in claim 2 wherein the composition is in the form of tablets or capsules.