DESC:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents [Amendment] Rules, 2006

COMPLETE SPECIFICATION
(See Section 10 and rule 13)

TITLE OF THE INVENTION
PHARMACEUTICAL COMPOSITION COMPRISING MIRABEGRON
APPLICANT:
(a) Name : ALKEM LABORATORIES LIMITED
(b) Nationality : India
(c) Address : ALKEM HOUSE,
SENAPATI BAPAT MARG, LOWER PAREL,
MUMBAI, MAHARASHTRA, INDIA, PIN CODE 400013
PREAMBLE TO THE DESCRIPTION

COMPLETE
The following specification particularly describes the invention and the manner in which is to be performed.

FIELD OF THE INVENTION:
The present invention relates to a pharmaceutical composition for oral administration containing a therapeutically effective amount of beta-3 adrenergic agonist such as Mirabegron or a pharmaceutically acceptable salt thereof, and a method for the preparation thereof. The invention also relates to the use of said composition for the treatment of Neurogenic detrusor overactivity (NDO) in pediatric patients aged 3 years and older.

BACKGROUND OF THE INVENTION:
Mirabegron is a beta-3 adrenergic agonist. The chemical name is 2-(2-aminothiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy- 2-phenylethyl]amino}ethyl)phenyl]acetamide having an empirical formula of C21H24N4O2S and a molecular weight of 396.51. The structural formula of mirabegron is:

Mirabegron is a white powder. It is practically insoluble in water (0.082 mg/mL). It is soluble in methanol and dimethyl sulfoxide. Mirabegron is considered to be a Class III compound according to the Biopharmaceutical Classification System (BCS). That means that it has high solubility and low permeability. Based on the assessment report of Betmiga® published by the European Medicines Agency, mirabegron is soluble in water between neutral to acidic pH.

Mirabegron is marketed as modified (extended) release tablets and granules for extended release suspension sold under the brand name of MYRBETRIQ® and MYRBETRIQ Granules.

Mirabegron is an agonist of the human beta-3 adrenergic receptor indicated for the treatment of overactive bladder disorder. Mirabegron relaxes the detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle by activation of beta-3 adrenergic receptor which increases bladder capacity.

US Patent No. 6346532 discloses Mirabegron or a salt thereof and process for its preparation. This patent, however, is silent about the crystal forms of Mirabegron.

US Patent No. 7342117 patent discloses two crystalline polymorphic forms of Mirabegron, the crystalline a-form and ß-form. Said patent discloses the process for preparation of a-form crystal and ß-form crystal of Mirabegron.
PCT publication No. WO2012/156998A2 discloses processes for the preparation of a-form and ß-form crystal of Mirabegron and pharmaceutical composition comprising thereof.

US Patent No. RE44872 discloses method of treating overactive bladder disorder using mirabegron or a salt thereof.

US Patent Nos. 10842780 and 11707451 discloses extended release composition of mirabegron and its use for treating overactive bladder.

US Patent No. 10058536 discloses composition comprising mirabegron with sodium polystyrene sulfonate and a hydrophobic substance such as magnesium stearate or calcium stearate.

Based on prior formulations, still there is a need to develop stable formulations of mirabegron which provides improved solubility, dissolution rate, stability and manufacturing process and patient compliance.

SUMMARY OF THE INVENTION:
The present invention provides a pharmaceutical composition comprising mirabegron or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

Another aspect of the invention, the pharmaceutical composition comprises mirabegron or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients selected from but not limited to diluents, ion exchange resins, binders, preservatives, suspending agents/ thickener, antifoaming agent, sweetening agents, lubricants/glidants, flavouring agents, and colouring agents.

Another aspect of the present invention provides a pharmaceutical composition comprising mirabegron or a pharmaceutically acceptable salt thereof, diluents, ion exchange resins, binders, preservatives, suspending agents/Thickener, antifoaming agent sweetening agents, lubricants/glidants, flavouring agents, and colouring agents.

In another aspect of the invention, an oral pharmaceutical composition comprising about 5 % to about 15 % w/w of mirabegron or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

In yet another aspect, there is provided a pharmaceutical composition comprising:
a) about 5 % to about 15 % w/w of mirabegron or pharmaceutically acceptable salt thereof;
b) about 85 % to about 95% w/w of pharmaceutically acceptable excipients; wherein, said pharmaceutical composition is in the form of granules for suspension.

In yet another aspect of the present invention provides pharmaceutical composition comprising:
a) about 5 % w/w to about 15 % w/w of mirabegron or pharmaceutically acceptable salt thereof;
b) about 45 % w/w to about 65 % w/w of diluent;
c) about 10 % w/w to about 30 % w/w of ion exchange resin;
d) about 1 % w/w to about 10 % w/w of binder;
e) about 0.2 % w/w to about 5 % w/w of preservative;
f) about 1 % w/w to about 20 % w/w of suspending agents;
g) about 0.5 % w/w to about 3 % w/w of sweetening agent;
h) about 0.2 % w/w to about 3 % w/w of antifoaming agent;
i) about 0.2 % w/w to about 3 % w/w of glidant;
j) about 0.5 % w/w to about 5 % w/w of lubricant; and
k) optionally other pharmaceutically acceptable excipients.

In yet another aspect of the present invention provides stable pharmaceutical composition is in the form of granules for suspension dosage form comprising:
a) about 5 % w/w to about 15 % w/w of mirabegron or pharmaceutically acceptable salt thereof;
b) about 45 % w/w to about 65 % w/w of diluent;
c) about 10 % w/w to about 30 % w/w of ion exchange resin;
d) about 1 % w/w to about 10 % w/w of binder;
e) about 0.2 % w/w to about 5 % w/w of preservative;
f) about 1 % w/w to about 20 % w/w of suspending agents;
g) about 0.5 % w/w to about 3 % w/w of sweetening agent;
h) about 0.2 % w/w to about 3 % w/w of antifoaming agent;
i) about 0.2 % w/w to about 3 % w/w of glidant;
j) about 0.5 % w/w to about 5 % w/w of lubricant; and
k) optionally other pharmaceutically acceptable excipients.
wherein said composition is stable for at least 6 months of storage at 25° C. and 60% relative humidity (RH).

In yet another aspect of the present invention provides a stable pharmaceutical composition comprising mirabegron, wherein the total impurity in the said pharmaceutical composition is not more than 2% w/w after subjecting the said pharmaceutical composition to a storage condition of 25°C/ 60% RH for a period of at least 1 month and also the amount of nitrosamine impurity is less than the FDA acceptable limit based on maximum daily dose of mirabegron. In yet another aspect of the invention, impurity can be one or more than one from unknown impurity (such as impurity 2), 4 hydroxy benzoic acid or mixture thereof.

In yet another aspect of the present invention provides stable pharmaceutical composition is in the form of granules for suspension dosage form comprising:
a) about 10 % w/w of mirabegron or pharmaceutically acceptable salt thereof;
b) about 55.71 % w/w of mannitol;
c) about 20 % w/w of sodium polystyrene sulfonate;
d) about 5 % w/w of hypromellose;
e) about 2.17 % w/w of mixture of methyl paraben and ethyl paraben;
f) about 3.37 % w/w of xanthan gum;
g) about 1.2 % w/w of acesulfame potassium;
h) about 0.54 % w/w of simethicone;
i) about 0.5 % w/w of colloidal silicon dioxide;
j) about 1.5 % w/w of talc; and
k) optionally other pharmaceutically acceptable excipients.

In yet another aspect of the present invention provides powder for oral suspension of mirabegron containing 8 mg/mL of mirabegron upon reconstitution comprising:
a) about 830 mg of mirabegron
b) about 3500 mg to about 5500 mg of mannitol;
c) about 1400 mg to about 1750 mg of sodium polystyrene sulfonate;
d) about 350 mg to about 480 mg of hypromellose;
e) about 120 mg to about 220 mg of mixture of methyl paraben and ethyl paraben;
f) about 240 mg to about 340 mg of xanthan gum;
g) about 50 mg to about 150 mg of acesulfame potassium;
h) about 30 mg to about 70 mg of simethicone;
i) about 30 mg to about 50 mg of colloidal silicon dioxide;
j) about 100 mg to about 150 mg of talc; and
k) optionally other pharmaceutically acceptable excipients.

In yet another aspect of the present invention provides powder for oral suspension of mirabegron containing 8 mg/mL of mirabegron upon reconstitution comprising:
a) about 8 mg/ml of mirabegron
b) about 44 mg/ml of mannitol;
c) about 16 mg/ml of sodium polystyrene sulfonate;
d) about 4 mg/ml of hypromellose;
e) about 1.75 mg/ml of mixture of methyl paraben and ethyl paraben;
f) about 2.7 mg/ml of xanthan gum;
g) about 0.1 mg/ml of acesulfame potassium;
h) about 0.4 mg/ml of simethicone;
i) about 0.4 mg/ml of colloidal silicon dioxide;
j) about 1.2 mg/ml of talc; and
k) optionally other pharmaceutically acceptable excipients.

In yet another aspect, the present invention relates to the process for preparation of a granules for suspension, wherein process comprises steps of:
a) All ingredients were weighed accurately.
b) Mirabegron was added to purified water under stirring to form uniform dispersion and dilute Hydrochloric acid was added to the drug dispersion with stirring to get clear solution.
c) Sodium polystyrene sulfonate was added to the drug solution obtained in step b) and continued stirring to get mirabegron-resin complex.
d) The mirabegron- resin complex obtained in step c) was dried at suitable temperature and sifted through suitable sieve.
e) Hypromellose was added to purified water under stirring to get clear solution and to this solution simethicone was added under stirring to get clear solution.
f) The mirabegron-resin complex obtained in step d) was granulated with mannitol, methyl paraben and ethyl paraben using the binder solution obtained in step e) in fluidized bed processor.
g) The granules obtained in step f) were dried and milled through suitable screen using co-mill.
i) The granules obtained in step g) were blended with colloidal silicon dioxide, acesulfame potassium and xanthan gum in suitable blender followed by lubrication with talc.
j) The granules obtained in step i) were filled in bottles.

In yet another aspect, the present invention relates to a pharmaceutical composition comprising mirabegron or pharmaceutically acceptable salt used for treatment of Neurogenic detrusor overactivity (NDO) in pediatric patients aged 3 years and older.

In yet another aspect, the present invention relates to a method of treating of Neurogenic detrusor overactivity (NDO) in pediatric patients aged 3 years and older by a pharmaceutical composition comprising mirabegron or pharmaceutically acceptable salt.

In yet another aspect, the present invention relates to a use of pharmaceutical composition comprising mirabegron or pharmaceutically acceptable salt for treatment of Neurogenic detrusor overactivity (NDO) in pediatric patients aged 3 years and older.

DESCRIPTION OF THE INVENTION:
The present invention can be more readily understood by reading the following description of the invention and study of the included examples.

The use of the word "a" or "an" when used in conjunction with the term "comprising" in the claims and/or the specification may mean "one," but it is also consistent with the meaning of "one or more," "at least one," and "one or more than one."

The term "about" as used herein means a deviation within 10%, more preferably within 5%, and even more preferably, within 2% of the numbers reported.

The term ‘‘stable’’ refers to formulations that substantially retain the labelled amount of the therapeutically active ingredient during storage for commercially relevant times, and the drug-related impurity contents and nitrosamine impurity in the formulations remain within acceptable limits.

The term “impurity” refers to undesired contents present or produced in a pharmaceutical composition.

The term “therapeutically effective amount” is defined to mean the amount or quantity of the active drug is sufficient to elicit an appreciable pharmacological response, when administered to the patient.

As used herein, the term "bioavailability" denotes the degree to which a drug or other substance becomes available to the target tissue after administration.

“Pharmaceutically acceptable excipient(s)” are components that are added to the pharmaceutical composition other than the active ingredient. Pharmaceutically acceptable excipient(s) includes, but not limited to, ion exchange resin, diluent, binder, disintegrant, lubricant/glidants, antioxidant, plasticizer, surfactants, solvent/vehicle, flavors or colorants, coating materials and any other excipient known to the art for making solid oral pharmaceutical composition.

The term ‘‘w/w’’ refers to total weight of substance/excipients with respect to total composition weight or the proportion of a particular substance within a mixture, as measured by weight or mass.

The term “excipient” means a pharmacologically inactive component such as a ion exchange resin, binder, solvent, diluent, disintegrant, carrier, lubricant, or the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe, inert, non-toxic and are acceptable for human use.

By the term “pharmaceutical composition” or “solid oral pharmaceutical composition" or "composition" or "formulation" as used herein refers to a solid dosage form comprising mirabegron suitable for administration such as a granule, hard or soft gelatin capsule, tablet, caplet, mini-tablets, pellets, pills, granules or powder for suspension, suspension and the like. The pharmaceutical dosage form can be prepared by methods known in the art, such as dry granulation or wet granulation or direct compression. The granules can be dried by any suitable technique known in the art, the preferred technique used is fluidized bed process technique. The compression of the blend to tablet cores can be carried out using a conventional tabletting machine or a rotary compression machine. The tablet cores may vary in shape and can be, for example, round, oval, oblong, cylindrical or any other suitable shape. The cores may also vary in size depending on the concentration of the therapeutic agent. The material obtained by suitable methods known in the art can be filled into sachets, bottles, capsules or made into tablets.

The term “active ingredient” or “active agent” or “drug” used interchangeably, is defined to mean active drug i.e. mirabegron and its salt, solvate, esters, isomers, polymorphs that induce a desired pharmacological or physiological effect.

The term “mirabegron” includes all pharmaceutically acceptable salts, esters, isomers, stereo isomers, crystalline and amorphous forms. Pharmaceutically acceptable salts of mirabegron include but not limited to oxalate, phosphate or acid phosphate, hydrochloride, hydrobromide, sulphate, mesylate, acetate, maleate, fumarate, lactate, tartrate, citrate, methanesulfonate, pamoate, palmitate, and gluconate salts.

The present invention provides a mirabegron or pharmaceutically acceptable salt thereof may be present in an amount of about 5 % w/w to about 15 % w/w, preferably about 8 % w/w to about 12 % w/w, more preferably about 9 % w/w to about 11 % w/w of the composition. The present invention also provides a pharmaceutical composition comprising mirabegron in an amount of about 8 mg/mL upon reconstitution.

The present invention provides a mirabegron or pharmaceutically acceptable salt thereof having D90 particle size in the range of 1 to 75 µm, D50 particle size in range of 1 to 30 µm and D10 particle size in range of 1 to 10 µm.

The present invention provides a pharmaceutical composition comprising mirabegron or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

Another aspect of the invention, the pharmaceutical composition comprises mirabegron or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients selected from the group consisting of diluents, ion exchange resins, binders, preservatives, suspending agents/Thickner, antifoaming agent, sweetening agents, lubricants/glidants, flavouring agents, and colouring agents.

In one aspect of the invention, an oral stable pharmaceutical composition comprising about 5 % w/w to about 15 % w/w of mirabegron or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, preferably about 8 % w/w to about 12 % w/w, more preferably about 9 % w/w to about 11% w/w of the composition.

In yet another aspect, there is provided a pharmaceutical composition comprising:
a) about 5 % w/w to about 15 % w/w of mirabegron or pharmaceutically acceptable salt thereof;
b) about 85 % w/w to about 95% w/w of pharmaceutically acceptable excipients; wherein, said pharmaceutical composition is in the form of granules for suspension.

Diluents according to the present invention are selected from, but not limited to, silicon dioxide, titanium dioxide, talc, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, mannitol, sorbitol or other sugar alcohols, isomalt, sucrose, lactose, and the like used either alone or in combinations thereof and the most preferably used diluent is mannitol. Diluent may be present in an amount of about 45 % w/w to about 65 % w/w, preferably about 50 % w/w to about 63% w/w, more preferably about 54 % w/w to about 60 % w/w of the composition.

Ion exchange resins according to the present invention are selected from, but not limited to, methacrylic acid divinyl benzene copolymer with Hydrogen ion, polacrilin potassium, calcium polystyrene Sulphate, sodium polystyrene sulphate. A preferred ion exchange resin is sodium polystyrene sulfonate. Ion exchange resins may be present in an amount of 10 % w/w to about 30 % w/w, preferably about 15 % w/w to about 25 % w/w of the composition, more preferably about 18 % w/w to about 22 % w/w of the composition.

Binders according to the present invention are selected from, but not limited to, starch, pregelatinized starch, povidone, hydroxy propyl cellulose, polyethylene glycol, sorbitol, hypromellose, and the like used either alone or in combinations thereof. A preferred binder of the present invention is hypromellose. Binder may be present in an amount of about 1 % w/w to about 10 % w/w, preferably about 2 % w/w to about 7 % w/w, more preferably about 3% w/w to about 6 % w/w of the composition.

The term “preservative,” as used herein, refers to an agent or mixture of agents that is used to protect a composition against antimicrobial (e.g., yeast, mold, bacteria) activity. Preservatives include, but are not limited to, benzoic acid, sodium benzoate, ethylenediaminetetraacetic acid, sorbic acid, benzalkonium chloride, butyl paraben, methyl paraben, ethylparaben, propyl paraben, sodium propionate, and the like used either alone or in combinations thereof. A preferred preservative of the present invention is a combination of methyl paraben and ethyl paraben. Preservative may be present in an amount of about 0.2 % w/w to about 5 % w/w, preferably about 1 % w/w to about 4 % w/w, more preferably about 0.4 % w/w to about 3 % w/w of the composition.

The term “suspending agent or viscosity enhancer,” as used herein, refers to an agent or a mixture of agents that increases the thickness of a liquid thereby keeping the active ingredient suspended to allow accurate dosing. Suspending agent include, but are not limited to, xanthan gum, guar gum, acacia, alginic acid, sodium alginate, propylene glycol alginate, carbomer, salts of carboxymethylcellulose, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, bentonite, carrageenan, sucrose, sorbitol, xylitol, dextrose, fructose, maltitol, gelatin, tragacanth, a polyvinyl alcohol, cetearyl alcohol, colloidal silicon dioxide, blend of microcrystalline cellulose and carboxymethylcellulose sodium, and the like used either alone or in combinations thereof. A preferred suspending agent of the present invention is xanthan gum. Suspending agent may be present in an amount of about 1 % w/w to about 20 % w/w, preferably about 2 % w/w to about 15 % w/w, more preferably about 3 % w/w to about 8 % w/w of the composition.

Suitable sweetening agents include, but are not limited to, natural sweeteners such as sugars e.g. fructose, glucose, sucrose, sorbitol or mixtures thereof and artificial sweeteners such as sodium saccharine, sucralose, sodium cyclamate, aspartame, acesulfame potassium and the like used either alone or in combinations thereof. A preferred sweetening agent of the present invention is acesulfame potassium. Sweetening agents may be present in an amount of about 0.5 % w/w to about 3 % w/w, preferably about 0.7 % w/w to about 2 % w/w, more preferably about 1.1 % w/w to about 1.7 % w/w of the composition.

Lubricants according to the present invention are selected from, but not limited to, magnesium stearate, calcium stearate, aluminium stearate, sucrose stearate, sucrose fatty acid ester, stearic acid, fumaric acid, palmitic acid, sodium stearyl fumarate, talc, and the like used either alone or in combinations thereof. Lubricants may be present in an amount of about of about 0.5 % w/w to about 5 % w/w, preferably about 1 % w/w to about 3 % w/w, more preferably about 1.5 % w/w to about 2.5 % w/w of the composition.

Glidants according to the present invention are selected from, but not limited to, colloidal silicon dioxide, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, and the like used either alone or in combinations thereof. Glidants may be present in an amount of about 0.2 % w/w to about 3 % w/w, preferably about 0.3 % w/w to about 2 % w/w, more preferably about 0.4 % w/w to about 1 % w/w of the composition.

The anti-foaming agent prevents the formation of any bubbles or foaming. Suitable antifoaming agents may be selected from silicone based antifoaming agent such as, simethicone or its emulsion or suspension, and non-silicone anti-foaming agents like polypropylene based polyether dispersions, castor oil, fatty alcohol esters, glycerides and a mixture thereof. The anti-foaming agent may be present in an amount from about 0.2 % w/w to about 3% w/w, preferably about 0.1 % w/w to about 2 % w/w, more preferably about 0.4 % w/w to about 1 % w/w of the composition.

A ‘‘Solvent/vehicle’’ is a substance that dissolves a solute (a chemically distinct liquid, solid or gas), resulting in a suspension or solution. Examples include but not limited to purified water, alcoholic solvents methanol, ethanol; ketones such as acetone, propanone; esters such as ethyl acetate, n-propyl acetate, isopropylacetate and n-butyl acetate and the like; ethers such as dimethylether, diethylether, methyltertiarybutylether, ethylmethylether, diisopropylether, and dioxane.

In another aspect of the invention, an oral pharmaceutical composition comprising about 5 % w/w to about 15 % w/w of mirabegron or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

In yet another aspect, there is provided a pharmaceutical composition comprising:
a) about 5 % w/w to about 15 % w/w of mirabegron or pharmaceutically acceptable salt thereof;
b) about 85 % w/w to about 95% w/w of pharmaceutically acceptable excipients; wherein, said pharmaceutical composition is in the form of granules for suspension.

In yet another aspect of the present invention provides pharmaceutical composition comprising:
a) about 5 % w/w to about 15 % w/w of mirabegron or pharmaceutically acceptable salt thereof;
b) about 45 % w/w to about 65 % w/w of diluent;
c) about 10 % w/w to about 30 % w/w of ion exchange resin;
d) about 1 % w/w to about 10 % w/w of binder;
e) about 0.2 % w/w to about 5 % w/w of preservative;
f) about 1 % w/w to about 20 % w/w of suspending agents;
g) about 0.5 % w/w to about 3 % w/w of sweetening agent;
h) about 0.2 % w/w to about 3 % w/w of antifoaming agent;
i) about 0.2 % w/w to about 3 % w/w of glidant;
j) about 0.5 % w/w to about 5 % w/w of lubricant; and
k) optionally other pharmaceutically acceptable excipients.

In yet another aspect of the present invention provides stable pharmaceutical composition is in the form of granules for suspension dosage form comprising:
a) about 5 % w/w to about 15 % w/w of mirabegron or pharmaceutically acceptable salt thereof;
b) about 45 % w/w to about 65 % w/w of diluent;
c) about 10 % w/w to about 30 % w/w of ion exchange resin;
d) about 1 % w/w to about 10 % w/w of binder;
e) about 0.2 % w/w to about 5 % w/w of preservative;
f) about 1 % w/w to about 20 % w/w of suspending agents;
g) about 0.5 % w/w to about 3 % w/w of sweetening agent;
h) about 0.2 % w/w to about 3 % w/w of antifoaming agent;
i) about 0.2 % w/w to about 3 % w/w of glidant;
j) about 0.5 % w/w to about 5 % w/w of lubricant; and
k) optionally other pharmaceutically acceptable excipients.
wherein said composition is stable for at least 6 months of storage at 25° C. and 60% relative humidity (RH).

In yet another aspect of the present invention provides a stable pharmaceutical composition comprising mirabegron, wherein the total impurity in the said pharmaceutical composition is not more than 2% w/w after subjecting the said pharmaceutical composition to a storage condition of 25°C/ 60% RH for a period of at least 1month and also the amount of nitrosamine impurity is less than the FDA acceptable limit based on maximum daily dose of mirabegron. In yet another aspect of the invention, impurity can be one or more than one from unknown impurity (such as impurity 2), 4 hydroxy benzoic acid or mixture thereof.

In yet another aspect of the present invention provides stable pharmaceutical composition is in the form of granules for suspension dosage form comprising:
a) about 10 % w/w of mirabegron or pharmaceutically acceptable salt thereof;
b) about 55.71 % w/w of mannitol;
c) about 20 % w/w of sodium polystyrene sulfonate;
d) about 5 % w/w of hypromellose;
e) about 2.17 % w/w of mixture of methyl paraben and ethyl paraben;
f) about 3.37 % w/w of xanthan gum;
g) about 1.2 % w/w of acesulfame potassium;
h) about 0.54 % w/w of simethicone;
i) about 0.5 % w/w of colloidal silicon dioxide;
j) about 1.5 % w/w of talc; and
k) optionally other pharmaceutically acceptable excipients.

In yet another aspect of the present invention provides powder for oral suspension of mirabegron containing 8 mg/mL of mirabegron upon reconstitution comprising:
a) about 830 mg of mirabegron
b) about 3500 mg to about 5500 mg of mannitol;
c) about 1400 mg to about 1750 mg of sodium polystyrene sulfonate;
d) about 350 mg to about 480 mg of hypromellose;
e) about 120 mg to about 220 mg of mixture of methyl paraben and ethyl paraben;
f) about 240 mg to about 340 mg of xanthan gum;
g) about 50 mg to about 150 mg of acesulfame potassium;
h) about 30 mg to about 70 mg of simethicone;
i) about 30 mg to about 50 mg of colloidal silicon dioxide;
j) about 100 mg to about 150 mg of talc; and
k) optionally other pharmaceutically acceptable excipients.

In yet another aspect of the present invention provides powder for oral suspension of mirabegron containing 8 mg/mL of mirabegron upon reconstitution comprising:
a) about 8 mg/ml of mirabegron
b) about 44 mg/ml of mannitol;
c) about 16 mg/ml of sodium polystyrene sulfonate;
d) about 4 mg/ml of hypromellose;
e) about 1.75 mg/ml of mixture of methyl paraben and ethyl paraben;
f) about 2.7 mg/ml of xanthan gum;
g) about 0.1 mg/ml of acesulfame potassium;
h) about 0.4 mg/ml of simethicone;
i) about 0.4 mg/ml of colloidal silicon dioxide;
j) about 1.2 mg/ml of talc; and
k) optionally other pharmaceutically acceptable excipients.

In yet another aspect of the present invention provides stable pharmaceutical composition is in the form of granules for suspension dosage form comprising: a) about 5 % w/w to about 15 % w/w of mirabegron or pharmaceutically acceptable salt thereof; b) about 85 % w/w to about 95 % w/w of of pharmaceutically acceptable excipients; wherein, said pharmaceutical composition is in the form of granules for suspension.

In yet another aspect, the present invention relates to the process for preparation of a granules for suspension, wherein process comprises steps of:
a) All ingredients were weighed accurately.
b) Mirabegron was added to purified water under stirring to form uniform dispersion and dilute Hydrochloric acid was added to the drug dispersion with stirring to get clear solution.
c) Sodium polystyrene sulfonate was added to the drug solution obtained in step b) and continued stirring to get mirabegron-resin complex.
d) The mirabegron- resin complex obtained in step c) was dried at suitable temperature and sifted through suitable sieve.
e) Hypromellose was added to purified water under stirring to get clear solution and to this solution simethicone was added under stirring to get clear solution.
f) The mirabegron- resin complex obtained in step d) was granulated with mannitol, methyl paraben and ethyl paraben using the binder solution obtained in step e) in fluidized bed processor.
g) The granules obtained in step f) were dried and milled through suitable screen using co-mill.
i) The granules obtained in step g) were blended with colloidal silicon dioxide, acesulfame potassium and xanthan gum in suitable blender followed by lubrication with talc.
j) The granules obtained in step i) were filled in bottles.

In yet another aspect, the present invention provides pH of pharmaceutical composition is in the range of 3.5-7.5.

In yet another aspect, the present invention provides water content of a pharmaceutical composition which is not more than 5%.

In yet another aspect, the present invention provides viscosity of a pharmaceutical composition which is between 50cps-150cps.

In yet another aspect, the present invention provides sedimentation volume of a pharmaceutical composition which is between 0.8 to 1.

In yet another aspect, the present invention provides reconstitution time of a pharmaceutical composition which is not more than 3 minutes.

In yet another aspect, the present invention provides a pharmaceutical composition comprising 8mg/mL of mirabegron upon reconstitution with purified water.

In yet another aspect, the present invention relates to the administration of a pharmaceutical composition by medicine dispensing device or filled in bottles.

In yet another aspect, the present invention relates to the administration of a particular dose of pharmaceutical composition is based on the total body weight of the patient.

In yet another aspect, the present invention provides a pharmaceutical composition of mirabegron, which is bioequivalent to the marketed mirabegron product.

In yet another aspect, the present invention provides a process for preparation of a stable, reproducible and bioequivalent pharmaceutical composition of mirabegron.

In yet another aspect, the present invention relates to a pharmaceutical composition comprising mirabegron or pharmaceutically acceptable salt used for treatment of Neurogenic detrusor overactivity (NDO) in pediatric patients aged 3 years and older.

In yet another aspect, the present invention relates to a pharmaceutical composition comprising mirabegron or pharmaceutically acceptable salt used for treatment of Neurogenic detrusor overactivity (NDO) in pediatric patients aged 3 years and older.

In yet another aspect, the present invention relates to method for treatment of Neurogenic detrusor overactivity (NDO) in pediatric patients aged 3 years and older by a pharmaceutical composition comprising mirabegron or pharmaceutically acceptable salt.

In yet another aspect, the present invention relates to a use of pharmaceutical composition comprising mirabegron or pharmaceutically acceptable salt for treatment of Neurogenic detrusor overactivity (NDO) in pediatric patients aged 3 years and older.

The composition of the invention can be packed into suitable packaging system e. g. Blister packs, strip packs, alu-alu packs, bottles such as glass and plastic bottles, etc.

Additionally, N-nitrosamine impurities are possible in the synthesis of mirabegron and its pharmaceutical salt thereof. The N-nitrosamine impurities may originate from any or all of the active pharmaceutical ingredient, excipients, pharmaceutical packaging materials, and/or manufacturing process and equipment. Examples of N-nitrosamine impurities include, but are not limited to, N-Nitroso mirabegron, N-Nitrosodimethyl amine (“NDMA”), N-Nitrosodiethyl amine (“NDEA”), N-Nitrosodiisopropylamine (“NDIPA”), N-Nitrosoethylisopropylamine (“NIPEA”), N-nitroso-N-methyl-4-aminobutyric acid (“NMBA”), N-Nitrosodibutylamine (“NDBA”), and N-Methyl-N-phenylnitrosamine (“NMPA”). N-nitrosamines are generally formed when a secondary or tertiary amine reacts with a nitrosating agent. While the amounts of the N-nitrosamine impurities in drugs is generally low, some levels have been above the US Food and Drug Administration’s acceptable daily limit, potentially exposing many people to a slightly increased risk of cancer. Because of the aforementioned health-related effects, stringent limitations have been placed upon the permissible amounts of N-nitrosamine impurities in drug products. Because of the exceptionally low allowable limits for N-nitrosamine impurities in these products it become important to control the nitrosamine impurities during synthesis of active pharmaceutical ingredient or drug formulation.
In an embodiment of the present invention the Nitrosamine impurities are controlled within the permissible limits as per FDA guidelines.

EXAMPLES
The present invention is illustrated below by reference to the following examples. However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the invention, and not to be construed as limiting the invention, as many variations thereof are possible without departing from the spirit and scope of the invention.

Example – 1: Mirabegron granules for extended release oral suspension
(8 mg/mL after reconstitution)

1A 1B 1C
## Ingredients mg/bottle % w/w mg/bottle % w/w mg/bottle %w/w
A. Mirabegron- Resin complexation
1 Mirabegron 830 10 830 10 830 10
2 Sodium polystyrene sulfonate 1660 20 1640 19.75 1680 20.24
3 Hydrochloric Acid Q.S. - Q.S. - Q.S. -
4 Purified water Q.S. - Q.S. - Q.S. -
B. Binder Preparation
5 Hypromellose 415 5 470 5.6 425 5.12
6 Simethicone 45 0.54 50 0.6 40 0.48
7 Purified water Q.S. - Q.S. - Q.S. -
C. Granulation
8 Mirabegron - Resin complex 2490 - 2490 - 2490 -
9 Mannitol 4624 55.71 4650 56 4580 55.18
10 Methyl paraben 140 1.69 130 1.56 135 1.62
11 Ethyl paraben 40 0.48 30 0.36 45 0.54
D. Blending
12 Acesulfame Potassium 100 1.20 90 1.08 110 1.32
13 Xanthan Gum 280 3.37 260 3.1 290 3.49
14 Colliodal Silicon dioxide 41.50 0.50 30 0.37 45 0.54
E. Lubrication
15 Talc 124.50 1.50 120 1.44 120 1.44
Weight of granules 8300 100 8300 100 8300 100

Manufacturing process for example 1A, 1B, and 1C:
a) All ingredients were weighed accurately.
b) Mirabegron was added to purified water under stirring to form uniform dispersion and dilute Hydrochloric acid was added to the drug dispersion with stirring to get clear solution.
c) Sodium polystyrene sulfonate was added to the drug solution obtained in step b) and continued stirring to get mirabegron- sodium polystyrene sulfonate complex.
d) The mirabegron- sodium polystyrene sulfonate complex obtained in step c) was dried at suitable temperature and sifted through suitable sieve.
e) Hypromellose was added to purified water under stirring to get clear solution and to this solution simethicone was added under stirring to get clear solution.
f) The mirabegron- sodium polystyrene sulfonate complex obtained in step d) was granulated with mannitol, methyl paraben and ethyl paraben using the binder solution obtained in step e) in fluidized bed processor.
g) The granules obtained in step f) were dried and milled through suitable screen using co-mill.
i) The granules obtained in step g) were blended with colloidal silicon dioxide, acesulfame potassium and xanthan gum in suitable blender followed by lubrication with talc.
j) The granules obtained in step i) were filled in bottles.

Stability Study: Stability study conducted on composition of example 1A in order to ensure the stable composition for longer period of time and data is given in Table 1 as below:

Table 1: Stability study results of example 1A at 25°C / 60% RH:
Parameters Initial 25°C/ 60% RH 25°C/ 60% RH
3M 6M
Assay (%) Mirabegron 101.1 97.2 99.5
Water Content (%) 1.64 1.08 0.73
Viscosity 89.5 97.52 98.31
pH 6.51 6.53 6.46
Sedimentation Volume 0.90 0.95 0.95
Reconstitution Time 1 minute 1 minute 1 minute
Dissolution (%)
15 Minute 24 28 23
4 Hrs 49 59 51
10 Hrs 82 85 84
Organic Impurities
Impurity 2 0.023 0.070 0.056
Total Degradation Products 0.273 0.387 0.318
4 Hydroxy Benzoic Acid ND ND ND
Particle Size of Reconstituted Suspension
D(10) 14.1 15.7 15.7
D(50) 58.7 65.9 64.3
D(90) 119 131 131

Table 2: Nitrosamine impurity study results of example 1A at 40?/75%RH:
Sr. No Impurity Name Impurity limt (ppm) Results
Initial 6Months 40?/75%RH
1 N-Nitroso Mirabegron 0.2 BDL (0.096) 0.12ppm
BDL: Below Detection Limit

All the impurity data at initial, 3 months and 6 months at 25°C/ 60% RH stability were found to be satisfactory; also the nitrosamine impurity data at initial and 6 months at 40?/75%RH stability was found to be satisfactory.

Although the inventions herein have been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and application of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described.

All publications, patents, and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference.

We claim:
1) A stable pharmaceutical composition for oral administration comprising mirabegron or pharmaceutically acceptable salt thereof and sodium polystyrene sulfonate, wherein pharmaceutical composition does not contain magnesium stearate and/or calcium stearate.

2) The stable pharmaceutical composition as claimed in claim 1, wherein the composition comprises mirabegron in an amount of about 5 % w/w to about 15 % w/w based on the total weight of the composition.

3) The stable pharmaceutical composition as claimed in claim 1, wherein the composition is in the form of suspension.

4) The stable pharmaceutical composition as claimed in claim 1, wherein the composition is prepared using wet granulation, dry granulation or direct compression method.

5) A stable pharmaceutical composition comprising:
a) about 10 % w/w of mirabegron or pharmaceutically acceptable salt thereof;
b) about 55.71 % w/w of mannitol;
c) about 20 % w/w of sodium polystyrene sulfonate;
d) about 5 % w/w of hypromellose;
e) about 2.17 % w/w of mixture of methyl paraben and ethyl paraben;
f) about 3.37 % w/w of xanthan gum;
g) about 1.2 % w/w of acesulfame potassium;
h) about 0.54 % w/w of simethicone;
i) about 0.5 % w/w of colloidal silicon dioxide;
j) about 1.5 % w/w of talc; and
k) optionally other pharmaceutically acceptable excipients.

6) A stable pharmaceutical composition comprising:
a) about 8 mg/ml of mirabegron
b) about 44 mg/ml of mannitol;
c) about 16 mg/ml of sodium polystyrene sulfonate;
d) about 4 mg/ml of hypromellose;
e) about 1.75 mg/ml of mixture of methyl paraben and ethyl paraben;
f) about 2.7 mg/ml of xanthan gum;
g) about 0.1 mg/ml of acesulfame potassium;
h) about 0.4 mg/ml of simethicone;
i) about 0.4 mg/ml of colloidal silicon dioxide;
j) about 1.2 mg/ml of talc
k) optionally other pharmaceutically acceptable excipients.

7) The stable pharmaceutical composition as claimed in any of the preceding claims, wherein the composition is stable for at least 24 hours at 25 ± 2°C / 60 ± 5 % relative humidity.

8) The stable pharmaceutical composition as claimed in any of the preceding claims, wherein the composition has less than 400 ng/day of N-Nitroso mirabegron impurity.

9) The stable pharmaceutical composition as claimed in any of the preceding claims, wherein the composition further comprises one of more excipients selected from the group consisting of mannitol, hypromellose, methyl paraben, ethyl paraben, xanthan gum, acesulfame potassium, simethicone, colloidal silicon dioxide, talc.

10) The stable pharmaceutical composition as claimed in any of the preceding claims, wherein the composition is indicated for the treatment of neurogenic detrusor overactivity.

Dated this 10th day of October 2024

Mr. Thirupathi Bendram
VP & Head - IPR
Alkem Laboratories Limited

,CLAIMS:We claim:
1) A stable pharmaceutical composition for oral administration comprising mirabegron or pharmaceutically acceptable salt thereof and sodium polystyrene sulfonate, wherein pharmaceutical composition does not contain magnesium stearate and/or calcium stearate.

2) The stable pharmaceutical composition as claimed in claim 1, wherein the composition comprises mirabegron in an amount of about 5 % w/w to about 15 % w/w based on the total weight of the composition.

3) The stable pharmaceutical composition as claimed in claim 1, wherein the composition is in the form of suspension.

4) The stable pharmaceutical composition as claimed in claim 1, wherein the composition is prepared using wet granulation, dry granulation or direct compression method.

5) A stable pharmaceutical composition comprising:
a) about 10 % w/w of mirabegron or pharmaceutically acceptable salt thereof;
b) about 55.71 % w/w of mannitol;
c) about 20 % w/w of sodium polystyrene sulfonate;
d) about 5 % w/w of hypromellose;
e) about 2.17 % w/w of mixture of methyl paraben and ethyl paraben;
f) about 3.37 % w/w of xanthan gum;
g) about 1.2 % w/w of acesulfame potassium;
h) about 0.54 % w/w of simethicone;
i) about 0.5 % w/w of colloidal silicon dioxide;
j) about 1.5 % w/w of talc; and
k) optionally other pharmaceutically acceptable excipients.

6) A stable pharmaceutical composition comprising:
a) about 8 mg/ml of mirabegron
b) about 44 mg/ml of mannitol;
c) about 16 mg/ml of sodium polystyrene sulfonate;
d) about 4 mg/ml of hypromellose;
e) about 1.75 mg/ml of mixture of methyl paraben and ethyl paraben;
f) about 2.7 mg/ml of xanthan gum;
g) about 0.1 mg/ml of acesulfame potassium;
h) about 0.4 mg/ml of simethicone;
i) about 0.4 mg/ml of colloidal silicon dioxide;
j) about 1.2 mg/ml of talc
k) optionally other pharmaceutically acceptable excipients.

7) The stable pharmaceutical composition as claimed in any of the preceding claims, wherein the composition is stable for at least 24 hours at 25 ± 2°C / 60 ± 5 % relative humidity.

8) The stable pharmaceutical composition as claimed in any of the preceding claims, wherein the composition has less than 400 ng/day of N-Nitroso mirabegron impurity.

9) The stable pharmaceutical composition as claimed in any of the preceding claims, wherein the composition further comprises one of more excipients selected from the group consisting of mannitol, hypromellose, methyl paraben, ethyl paraben, xanthan gum, acesulfame potassium, simethicone, colloidal silicon dioxide, talc.

10) The stable pharmaceutical composition as claimed in any of the preceding claims, wherein the composition is indicated for the treatment of neurogenic detrusor overactivity.