PRIORITY:

This application claims the benefit of Indian application number 202221029548 dated 23rd May 2022 and 3 ^rd May 2023 entitled, ‘A tablet composition of Mirabegron’, the contents of which are incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a controlled release pharmaceutical composition of Mirabegron or pharmaceutically acceptable salt(s) thereof.

BACKGROUND OF THE INVENTION

Mirabegron is a potent and selective agonist of the human beta-3 adrenergic receptor. Mirabegron is used as urinary antispasmodics and it is chemically known as 2-(2- aminothiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2 phenylethyl] amino }ethyl)phenyl] acetamide. The structural formula of mirabegron is as follows:

Mirabegron is also 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 as reported in PCT application number W004041276 (assigned to Yamanouchi Pharmaceutical Co., Ltd., referred to herein as WO’276).

European Patent Number EP2298752B1 (assigned to M/s Astellas Pharma Inc, referred to herein as EP’752) claims a crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2- phenylethyl) amino] ethyl] -acetanilide having a moisture-holding amount of not more than 0.2 % over the entire range of relative humidity from 5 % to 95 % and having main peaks at around 5.32, 8.08, 15.28, 17.88, 19.04, 20.20, 23.16 and 24.34 in the terms of 20(°) in the powder X-ray diffraction. European Patent Number EP1559427B1 (assigned to M/s Astellas Pharma Inc, referred to herein as EP’427) teaches use of Mirabegron in the treatment of overactive bladder.

United States Patent Number US10,842,780 (assigned to M/s Astellas Pharma Inc, referred to herein as US’780) teaches modified release compositions of Mirabegron with hydrogel forming polymer and an additive wherein the hydrogel-forming polymer is at least one compound selected from the group consisting of polyethylene oxide, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose sodium, hydroxyethyl cellulose, and a carboxyvinyl polymer, wherein the additive is at least one selected from the group consisting of polyethylene glycol, polyvinylpyrrolidone, D-mannitol, D-sorbitol, xylitol, lactose, sucrose, anhydrous maltose, D-fructose, dextran, glucose, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, polyoxyethylene sorbitan higher fatty acid ester, sodium chloride, magnesium chloride, citric acid, tartaric acid, glycine, 3-alanine, lysine hydrochloride, and meglumine. However, some of the additives have minor levels of toxicity and the other additives may act as laxative to some patients at the proposed concentration.

It is desirable to have a tablet composition comprising mirabegron or pharmaceutically acceptable salt(s) with less toxic and pharmacologically inactive excipients.

The amino group is present in mirabegron, especially secondary amines. Under acidic reactions there may be formation of nitrosamine in presence of secondary amines which is present in the mirabegron. Nitrosamines are carcinogenic which are not safe for patients.

The United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) recommend the acceptable limits for common nitrosamine impurities as enlisted below:

Further mirabegron contains N-Nitroso Mirabegron impurity which may be formed during synthesis of mirabegron or manufacturing of pharmaceutical composition of mirabegron. The N-Nitroso Mirabegron impurity which is having chemical structure as follows:

Therefore there is necessity to improve the controlled release pharmaceutical composition of mirabegron containing N-Nitroso Mirabegron impurity within the prescribed limits.

OBJECT OF THE INVENTION

The object of the present invention is to provide a controlled release pharmaceutical composition of Mirabegron or pharmaceutically acceptable salt(s).

SUMMARY OF THE INVENTION

A controlled release pharmaceutical composition for oral administration comprising a therapeutically effective amount of mirabegron or a pharmaceutically acceptable salt thereof, as an active ingredient, a hydrogel-forming polymer, as release controlling polymer, a colloidal agent, as a diluent and a pharmaceutically acceptable polymer of average molecular weight of less than 100,000, as a binder, wherein said active ingredient is released from said composition 30% or less after 2 hours, as measured in accordance with United States Pharmacopoeia in 900 m of a USP buffer having a pH of 6.8 at a basket rotation speed of 100 rpm.

A controlled release pharmaceutical composition of mirabegron or pharmaceutically acceptable salt thereof comprising a. hydrogel forming polymer is in the range of 5 to 50% by weight with respect to the total weight of the composition; b. colloidal agent is in the range of 15 to 65% by weight with respect to the total weight of the composition; c. pharmaceutically acceptable polymer of average molecular weight of less than 100,000 is in the range of 5 to 50% by weight with respect to the total weight of the composition; and d. further comprises at least one pharmaceutically acceptable excipient selected from lubricants, antioxidants and glidants;

Wherein the said composition releases 30% or less mirabegron after 2 hours, as measured in accordance with United States Pharmacopoeia in 900 mb of a USP buffer having a pH of 6.8 at a basket rotation speed of 100 rpm.

A controlled release pharmaceutical composition comprising a therapeutically effective amount of mirabegron or a pharmaceutically acceptable salt thereof comprises less than 250 ppm of nitrosamine related impurities.

The nitrosamine impurities of a controlled release pharmaceutical composition comprising a therapeutically effective amount of mirabegron or a pharmaceutically acceptable salt thereof is N-Nitroso Mirabegron.

DESCRIPTION OF THE INVENTION

A controlled release pharmaceutical composition for oral administration comprising a therapeutically effective amount of mirabegron or a pharmaceutically acceptable salt thereof, as an active ingredient, a hydrogel-forming polymer, as release controlling polymer, a colloidal agent, as a diluent and a pharmaceutically acceptable polymer of average molecular weight of less than 100,000, as a binder, wherein said active ingredient is released from said composition 30% or less after 2 hours, as measured in accordance with United States Pharmacopoeia in 900 mU of a USP buffer having a pH of 6.8 at a basket rotation speed of 100 rpm.

According to one embodiment of the present invention relates to a controlled release pharmaceutical composition of mirabegron or pharmaceutically acceptable salt thereof comprising a. hydrogel forming polymer is in the range of 5 to 50% by weight with respect to the total weight of the composition; b. colloidal agent is in the range of 15 to 65% by weight with respect to the total weight of the composition; c. pharmaceutically acceptable polymer of average molecular weight of less than 100,000 is in the range of 5 to 50% by weight with respect to the total weight of the composition; and d. at least one pharmaceutically acceptable excipient selected from lubricants, antioxidants and glidants;

Wherein the said composition releases 30% or less mirabegron after 2 hours, as measured in accordance with United States Pharmacopoeia in 900 mb of a USP buffer having a pH of 6.8 at a basket rotation speed of 100 rpm.

In another embodiment of the present invention, we have surprisingly found that controlled release pharmaceutical compositions comprising Mirabegron or pharmaceutically acceptable salt(s) wherein 30% or less mirabegron is released after 2 hours may be developed using pharmacologically inactive excipients such as colloidal agents. Colloidal agents enable penetration of water into the pharmaceutical composition.

The particle size of Mirabegron or pharmaceutically acceptable salt thereof used in the present invention may have particle size D(90) : NMT 35 microns, D(50): NMT 20 microns, D(10) : NMT 10 microns.

The said controlled release pharmaceutical composition is in the form of tablets, minitablets, pellets, capsules, granules or spheroids.

The controlled release pharmaceutical composition of mirabegron of the present invention comprises hydrogel forming polymer is selected from polyethylene oxide, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose sodium, hydroxyethyl cellulose and a carboxyvinyl polymer, or mixtures thereof.

In further aspect of the present invention the controlled release pharmaceutical composition of mirabegron comprises hydrogel forming polymer is polyethylene oxide with the average molecular weight approximately 2,000,000. The hydrogel forming polymer is in the range of 5 to 50%; preferably 10 to 40% and most preferred being 10 to 30% by weight with respect to the total weight of the composition.

The controlled release pharmaceutical composition of mirabegron of the present invention comprises colloidal agent selected from starch, pregelatinized starch, starch derivatives and gelatin, or mixtures thereof. Colloidal agents enable penetration of water into the pharmaceutical composition due to the fine particle size.

The colloidal agent is in the range of 15 to 65%; preferably 20 to 60% and most preferred being 20 to 50% by weight with respect to the total weight of the composition.

The controlled release pharmaceutical composition of mirabegron of the present invention comprises pharmaceutically acceptable polymer of average molecular weight of less than 100,000 selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose and methylcellulose, or mixtures thereof.

The pharmaceutically acceptable polymer of average molecular weight of less than 100,000 is in the range of 5 to 50%; preferably 10 to 45% and most preferred being 10 to 40% by weight with respect to the total weight of the composition.

In a further aspect of the present invention, a controlled release pharmaceutical composition of mirabegron or pharmaceutically acceptable salt thereof comprising a. hydrogel forming polymer preferably in the range of 10 to 40% weight by total weight of the composition; b. colloidal agent preferably in the range of 20 to 60% weight by total weight of the composition; c. pharmaceutically acceptable polymer of average molecular weight of less than 100,000 preferably in the range of 10 to 45% weight by total weight of the composition; and d. at least one pharmaceutically acceptable excipient selected from lubricants, antioxidants and glidants; wherein the said composition releases 30% or less mirabegron after 2 hours, as measured in accordance with United States Pharmacopoeia in 900 m of a USP buffer having a pH of 6.8 at a basket rotation speed of 100 rpm. The dissolution time of the tablet composition of the present invention is less than 30% or less mirabegron after 2 hours, preferably less than 20%.

The total weight of the tablet composition of the present invention is typically in the range of 100 to 400 mg and preferably 200 to 300 mg.

The tablet composition of the present invention may comprise pharmaceutical excipient(s) selected from lubricants, antioxidants and glidants.

The lubricants used in the present invention may be selected from stearic acid, calcium stearate, sodium stearyl fumarate, mixtures thereof. The lubricants may be in the range of 0.2 to 2% by weight with respect to the total weight of the tablet composition.

The antioxidants used in the present invention may be selected from butylated hydroxytoluene (BHT), butylhydroxyanisol (BHA), ascorbic acid, sodium ascorbate, sodium bisulfite, sodium pyrosulfite. The antioxidants may be in the range of 0.01 to 1.00% by weight with respect to the total weight of the tablet composition.

The tablets may be optionally coated by a film-coat. The coating agents may be selected from water soluble or water insoluble polymers.

The water soluble polymers used in the coating according to the present invention may be selected from hydroxypropylethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxybutyl cellulose, modified starch, polyvinyl alcohol, xanthan gum, or polyethylene oxide, polyvinylpyrrolidone (PVP), carboxyvinyl polymer, poloxamer, methylcellulose, carboxymethyl cellulose, polyvinyl alcohol, carrageenans, xanthan gum, and mixtures of one or more thereof.

The water insoluble polymers used in the coating according to the present invention may be selected from acrylic acid polymers, polymethacrylates or methacrylic acid copolymers, ethylcellulose, cellulose acetate, hydroxypropylcellulose succinate, hydroxypropylmethylcellulose succinate, alginate, acacia, chitosan, carmellose sodium, carmellose calcium, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, polyvinyl acetate phthalate, cellulose acetate trimellitate, shellac and derivatives and mixtures thereof.

Coating is done by using any conventional coating technique known in the art, such as spray coating in a conventional coating pan or fluidized bed processor or dip coating.

The pharmaceutical composition for e.g. Tablet composition according to the present invention is packaged in primary packaging material e.g. blisters, bottles. The tablet composition of the present invention is preferably packaged in PVC/PE/PVDC blisters (triplex) or Alu-Alu blisters or HDPE bottles.

The pharmaceutical composition of the present invention releases 30% or less of mirabegron after 2 hours. The test method is in accordance with United States Pharmacopoeia in 900 mb of a USP buffer having a pH of 6.8 at a basket rotation speed of 100 rpm.

According to another embodiment of the present invention is the process for the preparation of controlled release pharmaceutical composition of Mirabegron or pharmaceutically acceptable salts may be selected from wet granulation, dry granulation, direct compression, slugging, tabletting, coating, capsule filling, sachet filling and the like.

In further aspect of the present invention, a process for the preparation of a controlled release pharmaceutical composition for oral administration comprising a therapeutically effective amount of mirabegron or a pharmaceutically acceptable salt thereof, as an active ingredient, a hydrogel-forming polymer, as release controlling polymer, a colloidal agent, as a diluent and a pharmaceutically acceptable polymer of average molecular weight of less than 100,000, as a binder, wherein said active ingredient is released from said composition 30% or less after 2 hours, as measured in accordance with United States Pharmacopoeia in 900 mb of a USP buffer having a pH of 6.8 at a basket rotation speed of 100 rpm, wherein said process comprises the following steps: a. Sift mirabegron along with intragranular part. b. Granulate by using binder solution of polymer in suitable solvent. c. Blend the dried granules of step b. along with extragranular part. d. Lubricate with lubricant. Another embodiment of the present invention, mirabegron contains secondary amines. Under acidic reactions there may be formation of nitrosamine in presence of secondary amines which is present in the mirabegron. The formation of nitrosamines is also possible when secondary or tertiary amines react with nitrous acid. The nitrosamines impurities are carcinogenic in nature. Exposure to Nitrosamines, even in small amounts, poses a significant risk to patients. The presence of nitrosamines could form in a finished drug product over the drug product’s shelf life.

The nitrosamine impurity like N-nitrosodimethylamine (ND MA) is a genotoxic and carcinogenic agent in animals and is classified as probably carcinogenic to humans by the World Health Organization’s (WHO’s) International Agency for Research on Cancer (IARC).

The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) has published acceptable limits for common nitrosamine impurities of which NDMA and NMBA impurities having 96 ng/day limit and NDEA, NIPEA, NMPA, NDIPA, having 26.5 ng/day limits. These nitrosamine impurities can be detected by using analytical method like LCMS.

Therefore there is necessity to improve the controlled release pharmaceutical composition of mirabegron containing nitrosamine impurity.

In another embodiment of the present invention, a controlled release pharmaceutical composition comprising a therapeutically effective amount of mirabegron or a pharmaceutically acceptable salt thereof comprises less than 250 ppm of nitrosamine related impurities.

The nitrosamine impurities of a controlled release pharmaceutical composition comprising a therapeutically effective amount of mirabegron or a pharmaceutically acceptable salt thereof is N-Nitroso Mirabegron. Further, the detection of N-Nitroso Mirabegron impurity is analysed by using Liquid Chromatography Mass Spectroscopy (LCMS) method. BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 depicts the In-vitro dissolution profile comparison of Myrbetriq with Comparative Examples of Mirabegron Composition of the present invention as exemplified in Example 3.

The following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope of the invention.

EXAMPLES

Example 1: Comparative examples of mirabegron compositions as shown in Table 1

Table 1:

Example 2: Manufacturing Process

The comparative examples of controlled release pharmaceutical composition of Mirabegron as mentioned in the Table 1 are prepared by sifting intragranular part. Granulating fluid prepared by using suitable solvent as given in Table 1 respectively. Granulate the intragranular part using granulating fluid. Blend the dried granules of intragranular part along with extragranular part, further lubricate with lubricant.

Example 3: Dissolution Data

The comparative examples of controlled release pharmaceutical composition of Mirabegron Exla, Exlb & Exlc are subjected to a dissolution test carried out in accordance with a USP dissolution test apparatus as follows:

Dissolution Method: Basket method

Dissolution Media: 900 mb of pH 6.8 phosphate buffer (USP)

Rotation Speed: 100 RPM

The dissolution rate of comparative examples of controlled release pharmaceutical composition of Mirabegron after 2 hours is less than 30%.

Table 3: Provides the dissolution release profiles for Exla, Exlb & Exlc (Fig.1 .)

Example 4: Detection of N-Nitroso Mirabegron impurity by using Liquid Chromatography Mass Spectroscopy (LCMS) method. N-Nitroso Mirabegron impurity was analysed by using LCMS and the results are furnished below.

The above comparative examples are subjected for accelerated stability studies and it was observed that the N-Nitroso mirabegron impurities are stable and not increased during stability. The amount of the corresponding N-Nitroso mirabegron impurity formed in the present invention is significantly reduced to an acceptable level over the shelf-life of the product.