DESC:FIELD OF THE INVENTION:

Present invention relates to a pharmaceutical composition in the form of modified release tablet comprising of granules having Mirabegron, one or more water insoluble hydrophilic excipient and optionally antioxidant, wherein granules are free of polyethylene oxide; and extragranular portion having polyethylene oxide and one or more lubricant.

BACKGROUND OF THE INVENTION:

Mirabegron is a monocarboxylic acid amide disclosed in PCT application WO1999020607. A mirabegron containing modified release tablets are approved under the brand name Betmiga® in the EU comprising 25 and 50 mg of mirabegron for the management of overactive bladder.

Mirabegron belongs to BCS class III drugs as per Biopharmaceutical Classification System (BCS) and it is known that the bioavailability of mirabegron is affected by the presence of food in the GI tract. Therefore, to prevent this food effect, the Betmiga® modified release tablets are prepared which are based on an orally controlled absorption system (OCAS®).

OCAS® system of Mirabegron is described in WO2010038690 in which tablets are prepared by providing mirabegron with a high molecular weight polymer such as polyethylene oxide (PEO WSR N-60K) which forms hydrogel and a highly water soluble additive which ensures penetration of water into the pharmaceutical composition.

Other formulations of Mirabegron prepared using polyethylene oxide are disclosed in US2018185339, EP3653202, EP3292864, WO2021069944, WO2018169325, WO2020175897, WO2019009528 and WO2023113706. All of these formulations are based on mixing Mirabegron with polyethylene oxide, either alone or with water soluble additive or water insoluble hydrophilic additive.

It is known that polyethylene oxide forms gel like structure in presence of water. When composition of Mirabegron is prepared with polyethylene oxide without using water soluble additive such as PEG, agglomerates/ gum or gel like structure forms during wet granulation, which leads to improper granulation.

This is also known that polyethylene oxides are prone to degradation due to oxidation. To avoid this oxidation, prior art has suggested many ways such as use of special packaging or addition of high amount of anti-oxidants (WO2017186598) or by avoiding use of polyethylene oxide at all (WO2022125007 and WO2021028538). However, each of these solutions are associated with one or other problems such as use of high amount of antioxidant or avoidance of polyethylene oxide may increase complexity and variability of formulation, and this may also lead to a product which is not bioequivalent to Betmiga®. Further, changes in packaging may increase the cost of product.

Present invention has overcome the problem of prior art by providing a composition in the form of modified release tablet which provides desired release profile, wherein though polyethylene oxide is used but it is not used in close proximity of Mirabegron and thus does not promote oxidation of API. The present invention also solves the problems otherwise observed with wet granulation of mirabegron and polyethylene oxide.

SUMMARY OF THE INVENTION:

One aspect of present invention provides a modified release tablet comprising of
a. Granules comprising of Mirabegron, one or more water insoluble hydrophilic excipient and optionally an antioxidant, wherein granules are free of polyethylene oxide;
b. Extragranular portion comprising of polyethylene oxide having average molecular weight of 300000 and one or more lubricant.

Another aspect of present invention provides a modified release tablet comprising of
a. Granules comprising of Mirabegron, one or more water insoluble hydrophilic excipient and optionally an antioxidant, wherein granules are free of polyethylene oxide;
b. Extragranular portion comprising of polyethylene oxide having average molecular weight of 300000, polyethylene oxide having average molecular weight of 200000, polyethylene oxide having average molecular weight of 2000000 and one or more lubricant.

Another aspect of present invention provides a modified release tablet comprising of
a. Granules consisting of Mirabegron, one or more water insoluble hydrophilic excipient and optionally an antioxidant;
b. Extragranular portion comprising of polyethylene oxide having average molecular weight of 300000 and one or more lubricant;
wherein Mirabegron is 15% to 25% by total weight; water insoluble hydrophilic excipient is 4% to 55% by total weight and said polyethylene oxide is 25% to 40% by total weight of tablet.

Another aspect of present invention provides a modified release tablet comprising of
a. Granules comprising of Mirabegron, one or more water insoluble hydrophilic excipient and optionally an antioxidant, wherein granules are free of polyethylene oxide;
b. Extragranular portion comprising of polyethylene oxide having average molecular weight of 300000, polyethylene oxide having average molecular weight of 200000, polyethylene oxide having average molecular weight of 2000000 and one or more lubricant;
wherein Mirabegron is 8% to 30% by total weight, water insoluble hydrophilic excipient is 3% to 20% by total weight and total polyethylene oxide is 50% to 85% by total weight of tablet.

Yet, another aspect of present invention provides a modified release tablet comprising of
a. Granules consisting of 19% by weight of Mirabegron, 48% by weight of microcrystalline cellulose and 0.15% by weight of butylated hydroxytoluene;
b. Extragranular portion consisting of 28% by weight of polyethylene oxide having average molecular weight of 300000, 0.75% by weight of colloidal silicon dioxide and 1% by weight of magnesium stearate.

Yet, another aspect of present invention provides a modified release tablet comprising of
a. Granules comprising of 9% to 25% by weight of Mirabegron, 3% to 10% by weight of microcrystalline cellulose and optionally 0.01% to 0.5% by weight of butylated hydroxytoluene, based on total weight of tablet, wherein granules are free of polyethylene oxide;
b. Extragranular portion comprising of 30% to 40% by weight of polyethylene oxide having average molecular weight of 300000, 10% to 25% by weight of polyethylene oxide having average molecular weight of 200000, 12% to 24% by weight of polyethylene oxide having average molecular weight of 2000000 and 0.5% to 4% by weight of lubricant, based on total weight of tablet.

Another aspect of present invention provides a process of preparation of modified release tablet comprising of
a. Preparing granules comprising of Mirabegron, one or more water insoluble hydrophilic excipient and optionally an antioxidant by granulation, wherein granules are free of polyethylene oxide;
b. Adding extragranular portion comprising of polyethylene oxide having average molecular weight of 300000 and one or more lubricant.

Another aspect of present invention provides a process of preparation of modified release tablet comprising of
a. Preparing granules comprising of Mirabegron, one or more water insoluble hydrophilic excipient and optionally an antioxidant by granulation, wherein granules are free of polyethylene oxide;
b. Adding extragranular portion comprising of polyethylene oxide having average molecular weight of 300000, polyethylene oxide having average molecular weight of 200000, polyethylene oxide having average molecular weight of 2000000 and one or more lubricant.

Another aspect of present invention provides a process of preparation of modified release tablet comprising of
a. Preparing granules consisting of Mirabegron, one or more water insoluble hydrophilic excipient and an antioxidant by wet granulation;
b. Adding extragranular portion comprising of polyethylene oxide having average molecular weight of 300000 and one or more lubricant with granules of step a;
c. Compressing the blend or mixture of step b to form tablet(s);
d. Optionally, coating the tablet of step c;
wherein Mirabegron is 15% to 25% by total weight, water insoluble hydrophilic excipient is 40% to 55% by total weight and polyethylene oxide is 25% to 30% by total weight of tablet.

Another aspect of present invention provides a process of preparation of modified release tablet comprising of
a. Preparing granules comprising of Mirabegron, one or more water insoluble hydrophilic excipient and optionally an antioxidant by wet granulation, wherein granules are free of polyethylene oxide;
b. Adding extragranular portion comprising of polyethylene oxide having average molecular weight of 300000, polyethylene oxide having average molecular weight of 200000, polyethylene oxide having average molecular weight of 2000000 and one or more lubricant with granules of step a;
c. Compressing the blend or mixture of step b to form tablet(s);
d. Optionally, coating the tablet of step c;
wherein Mirabegron is 8% to 30% by total weight, water insoluble hydrophilic excipient is 3% to 20% by total weight and total polyethylene oxide is 50% to 85% by total weight of tablet.

These and other aspects of the invention may be more clearly understood from the following detailed description, from the examples given for illustrative and non-limiting purposes and the appended claims.

DETAILED DESCRIPTION OF THE INVENTION:

The following paragraphs detail various embodiments of the invention. For the avoidance of doubt, it is specifically intended that any particular feature(s) described individually in any one of these paragraphs (or part thereof) may be combined with one or more other features described in one or more of the remaining paragraphs (or part thereof). In other words, it is explicitly intended that the features described below individually in each paragraph (or part thereof) represent important aspects of the invention that may be taken in isolation and combined with other important aspects of the invention described elsewhere within this specification as a whole, and including the examples. The skilled person will appreciate that the invention extends to such combinations of features and that these have not been recited in detail here in the interests of brevity.

The use of the terms “a” and "an” and "the” and similar referents including “tablet” or “tablets” in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

The term “granules” as used herein refers to the granules or pellets prepared by using wet or dry granulation process. Wet granulation may include rapid mixing granulation or fluid bed granulation. Dry granulation includes roller compaction. In either of the case, Mirabegron is present in granules, wherein Mirabegron is added only in dry form. Preferably, granules are prepared using wet granulation process.

The term “extragranular portion” as used herein refers to the portion which is added to the granules of invention. Such extragranular portion is in the form of blend or mixture of excipients, which are preferably not granulated.

The term “free of polyethylene oxide” as used herein refers to granules prepared according to present invention, wherein polyethylene oxide is not added during granulation process.

The term “by total weight” or “by weight” are used interchangeably and such terms refer to the weight by total weight of tablet, unless the context requires otherwise. The total weight includes film coating as well, if present. The weight specified in any of the embodiments of present invention includes variation of ±10% of weight of tablet or ±5% of average weight of tablets.

The term “Molecular weight” as used herein in context of polyethylene oxide represents average molecular weight. The polyethylene oxide with different molecular weights or viscosity are defined in Handbook of Pharmaceutical excipients sixth edition 2009. The polyethylene oxide having average molecular weight of 300000 is Polyox WSR-N-750 having viscosity 600-1200 mPa (5% aq solution at 25°C). The polyethylene oxide having average molecular weight of 200000 is Polyox WSR-N80 having viscosity 55-90 mPa (5% aq solution at 25°C). The polyethylene oxide having average molecular weight of 2000000 is Polyox WSR-N60K having viscosity 2000-4000 mPa (2% aq solution at 25°C).

One embodiment of present invention provides a modified release tablet comprising of
a. Granules comprising of Mirabegron, one or more water insoluble hydrophilic excipient and optionally an antioxidant, wherein granules are free of polyethylene oxide;
b. Extragranular portion comprising of polyethylene oxide having average molecular weight of 300000 and one or more lubricant.

Another embodiment of present invention provides a modified release tablet comprising of
a. Granules comprising of Mirabegron, one or more water insoluble hydrophilic excipient and optionally an antioxidant, wherein granules are free of polyethylene oxide;
b. Extragranular portion comprising of polyethylene oxide having average molecular weight of 300000, polyethylene oxide having average molecular weight of 200000, polyethylene oxide having average molecular weight of 2000000 and one or more lubricant.

The modified release tablet according to embodiment hereinabove, wherein tablet comprises polyethylene oxide having average molecular weight of 300000 from 20% to 50% by weight, preferably 30% to 40% by weight of tablet; polyethylene oxide having average molecular weight of 200000 from 5% to 25% by weight, preferably 10% to 25% by weight of tablet and polyethylene oxide having average molecular weight of 2000000 from 5% to 30% by weight, preferably 12% to 24% by weight of tablet.

Yet, another embodiment of present invention provides a modified release tablet comprising of
a. Granules consisting of Mirabegron, one or more water insoluble hydrophilic excipient and optionally an antioxidant;
b. Extragranular portion consisting of polyethylene oxide having average molecular weight of 300000 and one or more lubricant.

Another embodiment of present invention provides a modified release tablet comprising of
a. Granules comprising of Mirabegron, one or more water insoluble hydrophilic excipient and optionally an antioxidant, wherein granules are free of polyethylene oxide;
b. Extragranular portion comprising of polyethylene oxide having average molecular weight of 300000, polyethylene oxide having average molecular weight of 200000, polyethylene oxide having average molecular weight of 2000000 and one or more lubricant;
wherein Mirabegron is 8% to 30% by total weight, water insoluble hydrophilic excipient is 3% to 20% by total weight and total polyethylene oxide is 50% to 85% by total weight of tablet.

Preferably, tablet according to embodiment hereinabove, wherein Mirabegron is 9% to 25% by total weight, water insoluble hydrophilic excipient is 3% to 10% by total weight and total polyethylene oxide is 60% to 80% by total weight of tablet.

Since granules comprising Mirabegron according to present invention do not contain polyethylene oxide, it will not lead to problem of stability of API and solves the problem of lump or gel formation during granulation. However, since Betmiga® tablets are prepared using OCAS technology wherein polyethylene oxide forms hydrogel and controls the release of API and thereby controls the food effect; composition of present invention wherein mirabegron would not be entrapped in hydrogel of polyethylene oxide, it becomes challenging to control the release of Mirabegron from the tablet similar to Betmiga®.

Inventions of present invention have surprisingly found that polyethylene oxide having average molecular weight of 300000 in combination with polyethylene oxide having average molecular weight of 200000 and polyethylene oxide having average molecular weight of 2000000, when used extragranularly, controls the release of Mirabegron from the tablet similar to Betmiga® and at the same time provides stable product. More surprisingly, these tablets of present invention do not require any additional release controlling agent in the granules.

Another embodiment of present invention provides a modified release tablet comprising of
a. Granules comprising of Mirabegron, one or more water insoluble hydrophilic excipient and optionally an antioxidant, wherein granules are free of polyethylene oxide;
b. Extragranular portion comprising of polyethylene oxide having average molecular weight of 300000 and one or more lubricant;
wherein Mirabegron is 15% to 25% by total weight, water insoluble hydrophilic excipient is 40% to 55% by total weight and polyethylene oxide is 25% to 30% by total weight of tablet.

Another embodiment of present invention provides a modified release tablet comprising of
a. Granules consisting of Mirabegron, one or more water insoluble hydrophilic excipient and optionally an antioxidant;
b. Extragranular portion comprising of polyethylene oxide having average molecular weight of 300000 and one or more lubricant;
wherein Mirabegron is 9% to 25% by total weight, water insoluble hydrophilic excipient is 4% to 55% by total weight and said polyethylene oxide is 25% to 40% by total weight of tablet.

Another embodiment of present invention provides a modified release tablet comprising of
a. Granules comprising of 8% to 30% by weight of Mirabegron, 3% to 20% by weight of microcrystalline cellulose and optionally 0.01% to 0.5% by weight of butylated hydroxytoluene, based on total weight of tablet, wherein granules are free of polyethylene oxide;
b. Extragranular portion comprising of 20% to 50% by weight of polyethylene oxide having average molecular weight of 300000, 5% to 25% by weight of polyethylene oxide having average molecular weight of 200000, 5% to 30% by weight of polyethylene oxide having average molecular weight of 2000000 and 0.5% to 4% by weight of lubricant, based on total weight of tablet.

Another embodiment of present invention provides a modified release tablet comprising of
a. Granules comprising of 9% to 25% by weight of Mirabegron, 3% to 10% by weight of microcrystalline cellulose and optionally 0.01% to 0.5% by weight of butylated hydroxytoluene, based on total weight of tablet, wherein granules are free of polyethylene oxide;
b. Extragranular portion comprising of 30% to 40% by weight of polyethylene oxide having average molecular weight of 300000, 10% to 25% by weight of polyethylene oxide having average molecular weight of 200000, 12% to 24% by weight of polyethylene oxide having average molecular weight of 2000000 and 0.75% to 3% by weight of lubricant, based on total weight of tablet.

A preferred embodiment of present invention provides a modified release tablet comprising of
a. Granules comprising of 9% or 19% by weight of Mirabegron, 6% to 9% by weight of microcrystalline cellulose and optionally 0.08% to 0.15% by weight of butylated hydroxytoluene, based on total weight of tablet, wherein granules are free of polyethylene oxide;
b. Extragranular portion comprising of 35% by weight of polyethylene oxide having average molecular weight of 300000, 12% to 22% by weight of polyethylene oxide having average molecular weight of 200000, 15% to 22% by weight of polyethylene oxide having average molecular weight of 2000000, 0.75% by weight of colloidal silicon dioxide and 1% by weight of magnesium stearate, based on total weight of tablet.

Inventors of present invention have surprisingly found that release of Mirabegron from the modified release tablet can be controlled with optimum concentration of combination of polyethylene oxide of grades having average molecular weight of 300000, 200000 and 2000000, without using it intragranularly.

Granules according to any of the embodiments of present invention comprises of Mirabegron and one or more water insoluble hydrophilic excipient. Preferably, said granules are free of any release controlling agents. More preferably, said granules are free of polyethylene oxide. Additionally, granules are free of cyclodextrin and free of hydrophilic base which includes 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, ß-alanine, lysine hydrochloride, and meglumine.

One or more water insoluble hydrophilic excipient of granules according to any of the embodiments of present invention is a polymer. Said polymer is preferably selected from microcrystalline cellulose or silicified microcrystalline cellulose. Amount of water insoluble hydrophilic excipient of invention can vary from 4% to 55% by weight of total weight of tablet. Preferably, tablet comprises about 3% to 20% or about 3% to 10% or about 6% to 9% or about 6% or 7% or about 48% of microcrystalline cellulose by total weight of tablet.

Mirabegron used for preparation of granules according to any of the embodiment of present invention is in crystalline form. Such crystalline form of Mirabegron can be selected from alpha form or beta form as described in EP2298752. Preferably, Mirabegron is in alpha crystalline from characterized by following 2?(º) values of powder X-ray diffraction spectrum- 5.32, 8.08, 15.28, 17.88, 19.04, 20.20, 23.16, 24.34 ±0.2, as measured according to the method and instrument described in EP2298752. Amount of Mirabegron may vary from 8% to 30%, preferably 9% to 25% by weight of total weight of tablet. Preferably, tablets comprise about 19% or 9% of mirabegron by total weight of tablet. In another embodiment tablet of present invention comprises 25 mg and 50 mg of Mirabegron.

Particle size of Mirabegron- D90 is less than 250 microns, preferably less than 100 microns, preferably less than 50 microns, most preferably less than 25 microns, as measured using laser diffraction method (Malvern MasterSizer 2000 or 3000).

Granules according to any of the embodiments of present invention can optionally contain an antioxidant. Such antioxidants are selected from group comprising of butylated hydroxytoluene (BHT), propyl gallate and sodium ascorbate. Preferably, antioxidant is butylated hydroxytoluene. Tablets or granules can have 0%-0.5% by weight of antioxidant. Preferably, antioxidants are in amount 0.01% to 0.5% by weight of total weight of tablet. More preferably, BHT is 0.01% to 0.4% or 0.01% to 0.2% or 0.08% to 0.15% or 0.06% or 0.08% or 0.15% by weight of total weight of tablet. Granules according to any of the embodiments of present invention are preferably free of antioxidants.

Extragranular portion according to any of the embodiments of present invention comprises a powdered mixture or lubricated blend comprises polyethylene oxide having average molecular weight of 300000. Such mixture or blend preferably comprise mixture of one or more other polyethylene oxide with different average molecular weight. Preferably, extragranular portion comprises polyethylene oxide having average molecular weight of 300000, polyethylene oxide having average molecular weight of 200000 and polyethylene oxide having average molecular weight of 2000000.

Polyethylene oxide having average molecular weight of 300000 of present invention can vary from 20% to 50%, preferably, 30% to 40% by total weight of tablet. It can be 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40% or any range in between, by total weight of tablet. Most preferably, polyethylene oxide having average molecular weight of 300000 is about 35% by total weight of tablet.

Polyethylene oxide having average molecular weight of 200000 of present invention can vary from 5% to 25%, preferably, 10% to 25% by total weight of tablet. It can be 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25% or any range in between, by total weight of tablet. Most preferably, polyethylene oxide having average molecular weight of 200000 is selected from about 19%, about 22% and about 13% by total weight of tablet.

Polyethylene oxide having average molecular weight of 2000000 of present invention can vary from 5% to 30%, preferably 12% to 24% by total weight of tablet. It can be 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or any range in between, by total weight of tablet. Most preferably, polyethylene oxide having average molecular weight of 2000000 is selected from 15.5% and 21% by total weight of tablet.

Therefore, in a preferred embodiment, extragranular portion according to present invention comprises about 35% by weight of polyethylene oxide having average molecular weight of 300000; about 22% by weight or about 19% by weight or about 13% by weight of polyethylene oxide having average molecular weight of 200000; about 15.5% by weight or about 21% by weight of polyethylene oxide having average molecular weight of 2000000; based on total weight of tablet.

Total polyethylene oxide present in extragranular portion ranges from 50% to 85%, preferably 60% to 80% or 65% to 85%, more preferably 65% to 80%, most preferably about 69% or about 82% or about 80% by weight of total weight of tablet. Such blend or mixture additionally comprises one or more lubricant(s).

Ratio of polyethylene oxide having average molecular weight of 200000 to polyethylene oxide having average molecular weight of 300000 ranges from 2:1 to 1:10, preferably 1:1 to 1:4, more preferably from 1:1.5 to 1:3, most preferably from 1:1.8 to 1:2.8. In an embodiment, ratio of polyethylene oxide having average molecular weight of 200000 to polyethylene oxide having average molecular weight of 300000 is about 1:2 or 1:3.

Ratio of polyethylene oxide having average molecular weight of 2000000 to polyethylene oxide having average molecular weight of 300000 ranges from 1:10 to 2:1, preferably 1:1 to 1:4, most preferably from 1:1.6 to 1:2.25. In an embodiment, ratio of polyethylene oxide having average molecular weight of 2000000 to polyethylene oxide having average molecular weight of 300000 is about 1:1.5 or 1:2.25.

Ratio of polyethylene oxide having average molecular weight of 200000 to polyethylene oxide having average molecular weight of 2000000 ranges from 6:1 to 1:6, preferably 2:1 to 1:3, more preferably from 1.5:1 to 1:2, most preferably from 1.2:1 to 1:1.65. In an embodiment, ratio of polyethylene oxide having average molecular weight of 200000 to polyethylene oxide having average molecular weight of 2000000 is about 1:1 or 1:1.5.

In another embodiment ratio of mirabegron: polyethylene oxide having average molecular weight of 300000 ranges from 1:1 to 1:4; preferably ratio is 1:1 to 1:2. Most preferably, ratio of mirabegron: polyethylene oxide having average molecular weight of 300000 is about 2:3 or 1:1.8 or 1:4.

In another embodiment of present invention, ratio of mirabegron: total polyethylene oxide ranges from 1:2 to 1:4.5 or 1:7 to 1:9; preferably ratio is 1:3 to 1:4 or 1:8 to 1:9. Most preferably, ratio of mirabegron : total polyethylene oxide is about 1:3.5 or 1:8.5.

In a preferred embodiment, extragranular portion is not granulated.

A lubricant according to present invention can be any excipient which helps in improving flowability or reducing sticking. Suitable lubricant can be selected from magnesium stearate, colloidal silicon dioxide and sodium stearyl fumarate. In a preferred embodiment lubricant comprises magnesium stearate and colloidal silicon dioxide.

Modified release tablet of invention may comprise 0.5 % to 4%, preferably 0.75% to 3% or 0.5% to 3% of lubricant by total weight of tablet. Preferably, tablet comprises 0.5% to 1.5% w/w of magnesium stearate and 0.5% to 1% w/w of colloidal silicon dioxide, by total weight of tablet. Most preferably, tablet comprises about 1% of magnesium stearate and about 0.75% of colloidal silicon dioxide, based on total weight of tablet.
Another embodiment of present invention provides a modified release tablet comprising of
a. Granules comprising of 19% by weight of Mirabegron, 48% by weight of microcrystalline cellulose and 0.15% of butylated hydroxytoluene;
b. Extragranular portion comprising of 28% by weight of polyethylene oxide having average molecular weight of 300000, 0.75% by weight of colloidal silicon dioxide and 1% by weight of magnesium stearate.
Additionally, tablet of present invention may comprise other pharmaceutical additive such as binder. Binders according to present invention includes hydroxypropyl cellulose, povidone, hydroxypropyl methylcellulose and the like. Preferable binder is hydroxypropyl cellulose. In a preferred embodiment, tablet of present invention or granules of present invention are free of binder.

The modified release tablet according to present invention can be optionally film coated. Such film coating comprises of water-soluble polymer such as hydroxypropyl methyl cellulose, a plasticizer such as glycerin and coloring agent such as iron oxide.

Film coating when used for the modified release tablet according to any of the embodiments of present invention is in amount 2% to 4% by weight of total weight of tablet, preferably film coating is about 3% by weight of total weight of tablet.

Hereinafter is provided a process of preparation of modified release tablet of present invention.

It is known in the pharmaceutical field that granules and thereby tablets can be prepared using either wet granulation or dry granulation technique, however wet granulation is more common and easy technique to employ. Prior art suggests that wet granulation of Mirabegron causes formation of impurities and therefore either dry granulation should be used for granulation of Mirabegron or non-aq solutions to be employed for granulation and coating of tablet to control the impurity generation as well as to get desired dissolution profile.
Inventors of present invention have solved the problem of prior art by providing the tablet containing granules which can be prepared with wet granulation however with acceptable impurity profile and use of alcoholic solution for coating is not required for such stable tablets.

An embodiment of present invention provides a process of preparation of modified release tablet comprising of
a. Preparing granules comprising of Mirabegron, one or more water insoluble hydrophilic excipient and optionally an antioxidant by granulation, wherein granules are free of polyethylene oxide;
b. Adding extragranular portion comprising of polyethylene oxide having average molecular weight of 300000 and one or more lubricant to the granules of step a;
c. Compressing the blend or mixture of step b to form tablet(s);
d. Optionally, coating the tablet of step c.

Another embodiment of present invention provides a process of preparation of modified release tablet comprising of
a. Preparing granules comprising of Mirabegron, one or more water insoluble hydrophilic excipient and optionally an antioxidant by wet granulation, wherein granules are free of polyethylene oxide;
b. Adding extragranular portion comprising of polyethylene oxide having average molecular weight of 300000, polyethylene oxide having average molecular weight of 200000, polyethylene oxide having average molecular weight of 2000000 and one or more lubricant;
c. Compressing the blend or mixture of step b to form tablet(s);
d. Optionally, coating the tablet of step c.

Another embodiment of present invention provides a process of preparation of modified release tablet comprising of
a. Preparing granules comprising of Mirabegron, one or more water insoluble hydrophilic excipient and optionally an antioxidant by wet granulation, wherein granules are free of polyethylene oxide;
b. Adding extragranular portion comprising of polyethylene oxide having average molecular weight of 300000 and one or more lubricant to the granules of step a;
c. Compressing the blend or mixture of step b to form tablet(s).

The process of preparation of modified release tablet according to embodiments hereinabove wherein Mirabegron is 15% to 25% by total weight; water insoluble hydrophilic excipient is 40% to 55% by total weight and polyethylene oxide is 25% to 30% by total weight of tablet. Alternatively, process of preparation of modified release tablet according to embodiments hereinabove wherein Mirabegron is 8% to 30% or 9% to 30% or 9% to 25% by total weight; water insoluble hydrophilic excipient is 3% to 20% or 3% to 10% by total weight; antioxidant, if present, is 0.01% to 0.5% by weight; polyethylene oxide having average molecular weight of 300000 is 20% to 50% or 30% to 40% by total weight; polyethylene oxide having average molecular weight of 200000 is 5% to 25% or 10% to 25% by total weight; polyethylene oxide having average molecular weight of 2000000 is 5% to 25% or 12% to 24% by total weight and lubricant is 0.5% to 4% or 0.75% to 3% by total weight of tablet.

The granulation process can be either wet granulation or dry granulation, preferably process according to invention is wet granulation. Wet granulation may include rapid mixing granulation or fluid bed granulation. Dry granulation includes roller compaction. Preferably, granulation is wet granulation which is rapid mixing granulation. Most preferably, granulation is aqueous wet granulation. During granulation, Mirabegron and one or more water insoluble hydrophilic excipient are dry mixed and granulation liquid comprising of water, optionally in combination with alcohol is added to dry mix to form granules. Granulation liquid may also comprise anti-oxidant, if used. Preferably, granulation liquid comprises of water, ethanol and optionally BHT. Granules are prepared by adding solution of said granulation liquid to said dry mix. Prepared granules are optionally dried in fluid bed dryer to achieve LoD of less than 3% by weight, preferably less than 2% by weight and solvent content of less than 5000ppm. Preferably, modified release tablet according to any of the embodiment of present invention is prepared by wet granulation process.

After granules are prepared, extragranular portion is added to the granules which comprises of one or more lubricant and polyethylene oxide having average molecular weight of 300000, preferably in combination with polyethylene oxide having average molecular weight of 200000 and polyethylene oxide having average molecular weight of 2000000. Preferably, granules are first mixed with first lubricant such as colloidal silicon dioxide followed by addition of polyethylene oxide(s). Obtained mixture is then lubricated with second lubricant magnesium stearate. The obtained blend or mixture is compressed to form a modified release tablet. The extragranular portion is prepared by mixing or blending polyethylene oxide having average molecular weight of 300000 and one or more lubricant or by mixing or blending polyethylene oxide having average molecular weight of 300000, polyethylene oxide having average molecular weight of 200000 and polyethylene oxide having average molecular weight of 2000000 and one or more lubricant.

Another embodiment of present invention provides a process of preparation of modified release tablet comprising of
a. Preparing granules consisting of Mirabegron, one or more water insoluble hydrophilic excipient and optionally an antioxidant by wet granulation;
b. Adding extragranular portion consisting of polyethylene oxide having average molecular weight of 300000 and one or more lubricant to the granules of step a;
c. compressing the blend or mixture of step b to form tablet(s);
a. wherein Mirabegron is 15% to 25% by total weight, water insoluble hydrophilic excipient is 40% to 55% by total weight and polyethylene oxide is 25% to 30% by total weight of tablet.

Another embodiment of present invention provides a process of preparation of modified release tablet comprising of
a. Preparing granules comprising of Mirabegron, one or more water insoluble hydrophilic excipient and optionally an antioxidant by wet granulation, wherein granules are free of polyethylene oxide;
b. Adding extragranular portion comprising of polyethylene oxide having average molecular weight of 300000, polyethylene oxide having average molecular weight of 200000, polyethylene oxide having average molecular weight of 2000000 and one or more lubricant;
c. compressing the blend or mixture of step b to form tablet(s);
b. wherein Mirabegron is 8% to 30% by total weight, water insoluble hydrophilic excipient is 3% to 20% by total weight and total polyethylene oxide is 50% to 85% by total weight of tablet.

Another embodiment of present invention provides a process of preparation of modified release tablet comprising of
a. Preparing granules consisting of Mirabegron, microcrystalline cellulose and optionally an antioxidant by wet granulation;
b. Adding colloidal silicon dioxide to the granules of step a;
c. Adding polyethylene oxide having average molecular weight of 300000, optionally in combination with polyethylene oxide having average molecular weight of 200000 and polyethylene oxide having average molecular weight of 2000000 to the mixture of step b;
d. Adding magnesium stearate to the mixture of step c;
e. compressing the blend or mixture of step d to form tablet(s);
f. Coating the tablet of step e.

Another embodiment of present invention provides a process of preparation of modified release tablet comprising of
a. Preparing granules comprising of Mirabegron, one or more water insoluble hydrophilic excipient and optionally an antioxidant by wet granulation, wherein granules are free of polyethylene oxide;
b. Adding extragranular portion comprising of polyethylene oxide having average molecular weight of 300000, polyethylene oxide having average molecular weight of 200000, polyethylene oxide having average molecular weight of 2000000 and one or more lubricant;
c. compressing the blend or mixture of step b to form tablet(s);
wherein Mirabegron is 9% to 25% by total weight; water insoluble hydrophilic excipient is 3% to 10% by total weight; antioxidant, if present is 0.01% to 0.5% by total weight; polyethylene oxide having average molecular weight of 300000 is 30% to 40% by total weight; polyethylene oxide having average molecular weight of 200000 is 10% to 25% by total weight; polyethylene oxide having average molecular weight of 2000000 is 12% to 24% by total weight and one or more lubricant is 0.75% to 3% by total weight of tablet.

Optionally, a film coating is applied over tablet obtained according to any of the embodiments described hereinabove. More specifically, the preferred Opadry® which comprises hydroxypropyl methyl cellulose, glycerin and iron oxide is applied over the tablets. Said film coating is applied over tablet by dissolving/ dispersing it in water or suitable solvent. Preferably, coating is dissolved in water.

Tablet according to present invention can be packed in any suitable packing such as blister or bottles. Blisters are preferably Alu-Alu and bottles are preferably HDPE.
The modified release tablet of present invention show an in-vitro dissolution profile wherein Mirabegron is release at least 10%, preferably 10-50% win 3 hours; at least 30%, preferably 30-70% within 5 hours and at least 80% within 10 hours when tablet is subjected to a dissolution study in 900 ml phosphate buffer (pH 6.8) using a USP apparatus 1 (basket) at 100 rpm at 37°C.

The invention will be further illustrated by the following examples, however, without restricting its scope to these embodiments.

EXAMPLES

Example 1
S. No. Ingredients % w/w Mg/tablet
1 Mirabegron 18.90 50.24
2 Microcrystalline cellulose 48.11 127.86
Granulating liquid
3 BHT 0.15 0.40
4 Ethanol - q.s.
5 Purified water - q.s.
Extragranular
6 Polyox N-750 28.22 75
7 Aerosil 200 Pharma 0.75 2
8 Magnesium stearate 0.94 2.5
Core tablet weight 258
Film Coating
1 Opadry 03M520002 yellow (Hydroxypropyl methyl cellulose, Glycerin, iron oxide 2.91 7.74
2 Purified water - q.s.
Total coated tablet weight 265.74

Butylated hydroxy toluene (BHT) was dissolved in ethanol under continuous stirring for 30 minutes or till clear solution is formed, followed by addition of purified water and stirring for 15 minutes to form granulation liquid. Mirabegron and Microcrystalline cellulose were co-sifted through 30 mesh ASTM and granulated with prepared granulation liquid in high shear mixer. Extra purified water was added during granulation till desired the granulometry of granules were achieved. Obtained wet granules were subjected to initial air drying for 5 to 10 minutes and finally, dried at inlet temperature of 65°C till target LOD achieved less than 2.0% w/w. The dried granules were sized through 30 mesh ASTM. A part of sized granules were mixed with aerosil 200 and sifted through 40 mesh ASTM and further mixed with remaining quantity of granules in a suitable blender for 15 minutes at 10 rpm. Sifted Polyethylene oxide (Polyox N-750) was mixed with these granules in a suitable blender for 15 minutes at 10 rpm followed by addition of magnesium stearate in a suitable blender for 5 minutes at 10 rpm. Final blend prepared was compressed in tablet of hardness at approx 110N. Further, the uncoated tablets were coated with 12.0% w/v dispersion of Opadry 03M520002 - yellow.

Examples 2, 3, 4 and 5

Ex 2 Ex 3 Ex 4 Ex 5
S. No. Ingredients %w/w mg/tab % /w mg/tab %w/w mg/tab %w/w mg/tab
1 Mirabegron 9.72 25.025 19.41 50.00 19.15 50.24 19.15 50.24
2 Microcrystalline cellulose (Vivapur 102) 3.32 8.55 6.66 17.15
6.47
16.66
6.47
16.66
Granulating liquid
3 BHT 0.03 0.075 0.058 0.15 0.16 0.40 0.16 0.40
4 Ethanol - q.s. - q.s. - q.s. - q.s.
5 Purified water - q.s. - q.s. - q.s. - q.s.
Extragranular
6 Polyox WSR N-750 36.98 95.22 34.95 90.00 34.95 90.00 32.62 84.00
7 Polyox WSR N60K 22.22 57.22 21.36 55.00 15.53 40.00 17.86 46.00
8 Polyox WSR N80 23.07 59.42 12.89 33.20 18.72 48.2 18.72 48.20
9 Aerosil 200 Pharma 0.78 2.0 0.78 2.0 0.78 2.0 0.78 2.0
10 Magnesium stearate 0.97 2.5 0.97 2.5 0.97 2.5 0.97 2.5
Core tablet weight 250 250 250
Film Coating
1 Opadry (HPMC, Glycerin, iron oxide) 2.91 7.5 2.91 7.5 2.91 7.5 2.91 7.5
2 Purified water - q.s. q.s. q.s. q.s.
Total coated tablet weight 257.5 257.5 257.5 257.5

In example 3, butylated hydroxy toluene (BHT) was dissolved in ethanol under continuous stirring till clear solution is formed, followed by addition of purified water and stirring for 15 minutes to form granulation liquid. Mirabegron and Microcrystalline cellulose were co-sifted through 16 mesh ASTM and granulated with prepared granulation liquid in high shear mixer. Obtained wet granules were subjected to initial air drying for 10 to 15 minutes and finally, dried at inlet temperature of 60±10°C till target LOD achieved less than 3.0% w/w and ethanol content of NMT 5000ppm. The dried granules were sized through 30 mesh ASTM. A part of sized granules were mixed with aerosil 200, sifted through 40 mesh ASTM and further mixed with remaining quantity of granules in a suitable blender for 15 minutes at 15 rpm. Sifted Polyethylene oxide (Polyox N-750, Polyox N80 and PolyoxN60K) were mixed with these granules in a blender followed by addition of magnesium stearate for 5 minutes at 15 rpm. Final blend prepared was compressed in tablets. Further, the uncoated tablets were coated with aq dispersion of Opadry. Examples 2, 4 and 5 were prepared similar to example 3.

Tablets prepared according to present invention were tested for dissolution and compared with reference drug Betmiga®. The dissolution test was carried out in 900 ml phosphate buffer (pH 6.8) using a USP apparatus 1 (basket) at 100 rpm at 37°C and 900 ml 0.1N HCl using a USP apparatus 1 (basket) at 100 rpm at 37°C. Results are summarized below:

Time (Hrs) Media 1 2 4 5 6 8
Betmiga® (B.No. 21L0527) in % mean Phosphate
Buffer 8 20 51 67 81 100
0.1 N HCl 20 38 71 84.5 95 102
Ex 4 in % mean Phosphate
Buffer 7 17 46 62 76 95
0.1 N HCl 23 43 79 92 98 99

The tablets prepared according to present invention, specifically having combination of polyethylene oxide having average molecular weight of 300000, polyethylene oxide having average molecular weight of 200000 and polyethylene oxide having average molecular weight of 2000000 extragranularly provide desired dissolution profile at gastrointestinal pH range.
Additionally, tablets of present invention were tested for stability in Alu-Alu pack using HPLC and it was observed that despite using wet granulation process with aq coating solution, tablets were stable for 3 months as given below.

Ex 4 Initial 3M 40ºC-75% RH
Unknown individual Impurity 0.15%
0.16%

Total Impurity 0.21% 0.21%
,CLAIMS:I/ We claim:

1. A modified release tablet comprising of
a. Granules comprising of Mirabegron, one or more water insoluble hydrophilic excipient and optionally an antioxidant, wherein granules are free of polyethylene oxide;
b. Extragranular portion comprising of polyethylene oxide having average molecular weight of 300000, polyethylene oxide having average molecular weight of 200000, polyethylene oxide having average molecular weight of 2000000 and one or more lubricant.

2. The modified release tablet as claimed in claim 1, wherein polyethylene oxide having average molecular weight of 300000 is 20% to 50% by total weight, polyethylene oxide having average molecular weight of 200000 is 5% to 25% by total weight and polyethylene oxide having average molecular weight of 2000000 is 5% to 30% by total weight of tablet.

3. The modified release tablet as claimed in claim 2, wherein polyethylene oxide having average molecular weight of 300000 is 30% to 40% by total weight, polyethylene oxide having average molecular weight of 200000 is 10% to 25% by total weight and polyethylene oxide having average molecular weight of 2000000 is 12% to 24% by total weight of tablet.

4. The modified release tablet as claimed in claim 1, wherein mirabegron is 8% to 30% by total weight, water insoluble hydrophilic excipient is 3% to 20% by total weight, antioxidant is 0.01 to 0.5% by total weight, polyethylene oxide having average molecular weight of 300000 is 20% to 50% by total weight, polyethylene oxide having average molecular weight of 200000 is 5% to 25% by total weight, polyethylene oxide having average molecular weight of 2000000 is 5% to 30% by total weight and lubricant is 0.5% to 4% by total weight of tablet.

5. The modified release tablet as claimed in claim 4, wherein mirabegron is 9% to 25% by total weight, water insoluble hydrophilic excipient is 3% to 10% by total weight, antioxidant is 0.01% to 0.5% by total weight, polyethylene oxide having average molecular weight of 300000 is 30% to 40% by total weight, polyethylene oxide having average molecular weight of 200000 is 10% to 25% by total weight, polyethylene oxide having average molecular weight of 2000000 is 12% to 24% by total weight and lubricant is 0.75% to 3% by total weight of tablet.

6. The modified release tablet as claimed in any of the preceding claims, wherein modified release tablet is prepared by wet granulation process.

7. The modified release tablet as claimed in any of the preceding claims, wherein tablet is free of binder.

8. A process of preparation of modified release tablet comprising of
a. Preparing granules comprising of Mirabegron, one or more water insoluble hydrophilic excipient and optionally an antioxidant by wet granulation, wherein granules are free of polyethylene oxide;
b. Adding extragranular portion comprising of polyethylene oxide having average molecular weight of 300000, polyethylene oxide having average molecular weight of 200000, polyethylene oxide having average molecular weight of 2000000 and one or more lubricant;
c. Compressing the blend or mixture of step b to form tablet(s);
d. Optionally, coating the tablet of step c.

9. The process of preparation as claimed in claim 8, wherein polyethylene oxide having average molecular weight of 300000 is 20% to 50% by total weight, polyethylene oxide having average molecular weight of 200000 is 5% to 25% by total weight, polyethylene oxide having average molecular weight of 2000000 is 5% to 30% by total weight of tablet.

10. The process of preparation as claimed in claim 8, mirabegron is 8% to 30% by total weight, water insoluble hydrophilic excipient is 3% to 20% by total weight, antioxidant is 0.01 to 0.5% by total weight, polyethylene oxide having average molecular weight of 300000 is 20% to 50% by total weight, polyethylene oxide having average molecular weight of 200000 is 5% to 25% by total weight, polyethylene oxide having average molecular weight of 2000000 is 5% to 30% by total weight and lubricant is 0.5% to 4% by total weight of tablet.