DESC:TITLE OF THE INVENTION: Mirabegron complex

FIELD OF THE INVENTION
The present invention relates to novel complex of Mirabegron with cyclic oligosaccharides and process of its preparation. The invention further relates to a pharmaceutical composition of novel complex of Mirabegron and pharmaceutically acceptable excipients.

BACKGROUND OF THE INVENTION
Mirabegron is designated chemically as 2-(2-Aminothiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide. The chemical structure of Mirabegron is represented by the following formula:

Mirabegron is an agonist of the human beta-3 adrenergic receptor (AR). It is indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency. Mirabegron is generally administered in low drug doses, in particular tablets containing 25 or 50 mg of Mirabegron.

U.S. patent no. 6,346,532 B1 discloses Mirabegron or salt thereof and process for its preparation.

U.S. patent no. 7,342,117 B2 discloses a-form crystal and ß-form crystal of Mirabegron and composition of a-form crystal and ß-form crystal of Mirabegron.

Indian patent application no. 1475/DEL/2015 discloses a process of preparing a stable pharmaceutical composition comprising the steps of: dissolving Mirabegron in a solvent(s); evaporating the solution by spraying on the dry mix bed consisting of polymer and diluent and formulating the desired formulation using formulation techniques.

U.S. patent application no. US2015/0224087 A1 discloses a solid dispersion of Mirabegron prepared by either hot melt extrusion method or use of amorphous silica or solvent removal process. Solvent removal process further includes use of antisolvent, spray drying and freeze drying methods.

European patent application no. EP3184516 A1 discloses the crystalline form I and II of inclusion complex of Mirabegron with ß-Cyclodextrin.

The present inventions relates to Novel complex of Mirabegron.

OBJECTIVES OF THE INVENTION
The principal object of this invention is novel complex Mirabegron with cyclic oligosaccharide and the process for the preparation of the same. A further objective of the invention provides pharmaceutical composition of novel complex of Mirabegron with cyclic oligosaccharides with pharmaceutically acceptable excipients.

SUMMARY OF THE INVENTION
The present inventions relates to novel complex of Mirabegron.
The present invention relates to novel complex of Mirabegron with cyclic oligosaccharides.

The present invention relates to novel complex of Mirabegron with cyclic oligosaccharides wherein cyclic oligosaccharides is Cyclodextrins.

The present invention relates to novel amorphous complex of Mirabegron with cyclic oligosaccharides.
One of the aspects of the present invention provides a novel complex of Mirabegron with cyclic oligosaccharides in the molar ratio of 2.5:1 to 4:1.

The present inventions relates to process for preparation of novel complex of Mirabegron.

The present invention relates to pharmaceutical composition of novel complex of Mirabegron with cyclic oligosaccharides and pharmaceutically acceptable excipients.

The present invention relates to pharmaceutical composition of novel complex of Mirabegron with cyclic oligosaccharides in the molar ratio of 2.5:1 to 4:1 and pharmaceutically acceptable excipients.

The present invention relates to pharmaceutical composition of novel amorphous complex of Mirabegron with cyclic oligosaccharides in the molar ratio of 2.5:1 to 4:1 and pharmaceutically acceptable excipients.

The present invention relates to pharmaceutical composition of novel complex of Mirabegron with cyclic oligosaccharides in the molar ratio of 2.5:1 to 4:1 and pharmaceutically acceptable excipients selected from binders, fillers or diluents, lubricants, glidants, disintegrants, antioxidants, polymers.

The present invention relates to pharmaceutical composition of novel amorphous complex of Mirabegron with cyclic oligosaccharides in the molar ratio of 2.5:1 to 4:1 and pharmaceutically acceptable excipients selected from binders, fillers or diluents, lubricants, glidants, disintegrants, antioxidants, polymers.

The present invention relates to pharmaceutical composition of novel complex of Mirabegron with cyclic oligosaccharides in the molar ratio of 2.5:1 to 4:1 and pharmaceutically acceptable excipients selected from 5 to 50% by weight of polymer, 10 to 30% by weight of filler or diluent, 3 to 12 % by weight of binder, 2 to 5 % by weight of glidants, 1 to 5 % of lubricant, 0 to 0.05 % by weight of antioxidant and 0 to 5 % by weight of disintegrant.

The present invention relates to pharmaceutical composition of novel amorphous complex of Mirabegron with cyclic oligosaccharides in the molar ratio of 2.5:1 to 4:1 and pharmaceutically acceptable excipients selected from 5 to 50% by weight of Polymer, 10 to 30% by weight of filler or diluent, 3 to 12 % by weight of binder, 2 to 5 % by weight of glidants, 1 to 5 % of lubricant, 0 to 0.05 % by weight of antioxidant and 0 to 5 % by weight of disintegrant.

The present invention also provides a process for preparation of pharmaceutical composition of Mirabegron complex with pharmaceutically acceptable excipients.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 illustrates an X-ray powder diffraction pattern of novel complex of Mirabegron with Hydroxy propyl beta cyclodextrin prepared as per example 1.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an efficient, economical simple and commercially viable complex of Mirabegron with cyclic oligosaccharides.

One of the aspects of present invention provides a novel amorphous complex of Mirabegron with cyclic oligosaccharides. The amorphous complex of Mirabegron with Hydroxy propyl beta cyclodextrin is illustrated in figure 1.

Another aspect of the present invention provides a process for preparation of Mirabegron complex which comprises,
a) mixing Mirabegron & cyclic oligosaccharides in molar ratio of 2.5:1 to 4:1 in a solvent to get clear solution;
b) isolating the complex by removal of the solvent from the solution;
c) optionally, mixing of isolated complex with suitable pharmaceutically acceptable excipients.

As referred herein, the “Mirabegron” can be crystalline, amorphous, mixture of crystalline and amorphous, solvate or hydrate or pharmaceutically acceptable salt.

An essential component of the compositions used for the present invention is that they comprise a cyclic oligosaccharide, or mixtures of different cyclic oligosaccharides. As used herein, the term “cyclic oligosaccharide” means a cyclic structure comprising six or more saccharide units. Preferred for use herein are cyclic oligosaccharides having six, seven or eight saccharide units and mixtures thereof, more preferably six or seven saccharide units and even more preferably seven saccharide units. It is common in the art to abbreviate six, seven and eight membered cyclic oligosaccharides to a, ß and ? respectively.

The cyclic oligosaccharide of the compositions used for the present invention may comprise any suitable saccharide or mixtures of saccharides. The cyclic oligosaccharides that may be used herein but not limited to a-cyclodextrins, ß-cyclodextrins, ?-cyclodextrins and the hydroxypropyl, hydroxyethyl, dihydroxypropyl, glucosyl, maltosyl, methylated and sulfobutyl ether derivatives of a-, ß-, and ?-cyclodextrin, and their mixtures.

As referred herein, the term “Mirabegron complex” can be used interchangeably with “complex of Mirabegron”, which may be but not limited to inclusion complex of Mirabegron with cyclic oligosaccharide or Mirabegron is in mixture with cyclic oligosaccharide or Mirabegron is in dispersion with cyclic oligosaccharide.

In one of the aspect of the present invention, the molar ratio of Mirabegron to cyclic oligosaccharides is 2.5:1 to 4:1 preferably is 4:1 or more preferably 3:1 most preferably 3.5:1.
Suitable solvent that may be selected from water or alcoholic solvent or mixture of thereof or more preferred alcoholic solvent is methanol.

Suitable techniques which may be used for the removal of the solvent include using any conventional method; preferably spray drying, freeze drying (lyophilisation), atmospheric distillation, vacuum distillation, and the like, or any other suitable technique.

Another aspect of the present invention provides a pharmaceutical composition of novel Mirabegron complex with and pharmaceutically acceptable excipients.

In yet another aspect, the present invention provides a pharmaceutical composition of novel amorphous Mirabegron complex with and pharmaceutically acceptable excipients.

In yet another aspect, the present invention provides process for the preparation of pharmaceutical composition of novel Mirabegron complex which comprises,
a) dispensing of the excipients in fluid bed processor;
b) dissolving Mirabegron and suitable cyclic oligosaccharides in suitable solvent under stirring to get clear solution;
c) granulating excipients in step a) with solution of step b) in Fluid Bed Processor;
d) lubricating the granules of step c);
e) granulates of step d) can be further compressed to tablet or filled in a capsule;
f) optionally tablet can be coated with suitable coating agent.

As referred herein, the "pharmaceutical composition" according to present invention may be but not limited to powders, pellets, beads, granules, tablets, compacts, capsules, microcapsules, tablets in capsules.

The pharmaceutical compositions according to present invention, in general comprise of one or more excipients. Examples of pharmaceutical excipients include, but are not limited to binders, fillers or diluents, lubricants, glidants, disintegrants, antioxidants, polymers.

In another aspect, the pharmaceutical composition according to present invention comprises 15 to 30% by weight of Mirabegron, 15 to 30% by weight of cyclic oligosaccharides, 5 to 50% by weight of polymer, 10 to 30% by weight of filler or diluent, 3 to 12 % by weight of binder, 2 to 5 % by weight of glidants, 1 to 5 % of lubricant, 0 to 0.05 % by weight of antioxidant and 0 to 5 % by weight of disintegrant.

As referred herein, the “% by weight” is calculated on the basis of total weight of pharmaceutical composition.

All excipients can be used at levels well known to the persons skilled in the art.
Binders may be selected from, but are not limited to, starches such as potato starch, wheat starch, corn starch; microcrystalline cellulose, celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, sodium carboxy methyl cellulose; natural gums like acacia, alginic acid, guar gum; liquid glucose, dextrin, polyvinylpyrrolidone, poly-N-vinyl amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth, combinations thereof; more preferably selected from polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, sodium carboxy methyl cellulose or mixture thereof.

Fillers or diluents, may be selected from, but are not limited to, carbohydrates, confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose, starch, lactose, xylitol, sorbitol, microcrystalline cellulose, calcium carbonate, calcium phosphate dibasic or tribasic, calcium sulphate, and the like and other materials known to one of ordinary skill in the art and combinations thereof; more preferably selected from lactose and microcrystalline cellulose or combination thereof.
Lubricants may be selected from, but are not limited to, those conventionally known in the art such as magnesium stearate, aluminum stearate or calcium stearate or zinc stearate, glyceryl behenate, mineral oil, sodium stearyl fumarate, stearic acid and combinations thereof; more preferably selected from Magnesium stearate and stearic acid.

Glidants may be selected from, but are not limited to, silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel and other materials known to one of ordinary skill in the art and combinations thereof; more preferably selected from colloidal silicon dioxide and talc.

Disintegrant which may be selected from but are not limited to alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, guar gum, magnesium aluminium silicate, sodium alginate, sodium starch glycolate and starches and other materials known to one of ordinary skill in the art and combinations thereof; more preferably selected from starch and sodium starch glycolate.
Polymer which may be selected from but are not limited to polyethylene oxide (PEO) compounds or poly ethylene glycol or cellulosic polymers or polyacrylic acid polymers or meth acrylic acid co-polymers; more preferably polyethylene oxide or poly ethylene glycol or cellulosic polymers or polyacrylic acid polymers or meth acrylic acid co-polymers or mixture thereof. The polyethylene oxide, those preferably used in the context of the invention are PEO WSR 303 and N6OK products, more especially PEO WSR N-10 or WSR N-80 or WSR N-750 or WSR-205 or WSR-1105 or WSR N-12K or WSR N-60K or WSR-301 or WSR Coagulant or WSR-303. The ethylene glycol polymers those preferably used in the context of the invention are polyethylene glycol (PEG) such as, for example, PEG 200 or PEG 400 or PEG 600 or PEG 2000 or PEG 4000 or PEG 6000 or PEG 8000. Cellulosic polymers used in the context of the invention are hydroxypropyl methyl cellulose or hydroxypropyl cellulose or ethyl cellulose or hydroxyethyl cellulose. Polyacrylic acid used in the context of the invention is Carbopol 934 or Carbopol 1342 or Carbopol ETD 2020 and meth acrylic acid co-polymers, for example Eudragit EPO or Eudragit L3OD or Eudragit RL or Eudragit RS.
Antioxidant which may be selected from but are not limited to ascorbic acid or salt thereof, derivatives of vitamin E, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), propylgallate, sodium bisulphite; more preferably butylhydroxyanisole (BHA) and butylhydroxytoluene (BHT).
The solvents used according to the invention are selected from water or alcoholic solvent or mixture thereof.

The Pharmaceutical composition may optionally be coated using coating agents, plasticizers, opacifier, colouring agent and suitable solvents known to one of ordinary skill in the art.

In another aspect, the present invention provides a pharmaceutical composition of novel complex of Mirabegron with cyclic oligosaccharides in the molar ratio of 2.5:1 to 4:1 and pharmaceutically acceptable excipients selected from binders, fillers or diluents, lubricants, glidants, disintegrants, antioxidants, polymers.

In another aspect, the present invention provides a pharmaceutical composition of novel amorphous complex of Mirabegron with cyclic oligosaccharides in the molar ratio of 2.5:1 to 4:1 and pharmaceutically acceptable excipients selected from binders, fillers or diluents, lubricants, glidants, disintegrants, antioxidants, polymers.

In yet another aspect, the present invention provides a pharmaceutical composition of novel complex of Mirabegron with cyclic oligosaccharides in the molar ratio of 2.5:1 to 4:1 and pharmaceutically acceptable excipients selected
from 5 to 50% by weight of polymer, 10 to 30% by weight of filler or diluent, 3 to 12 % by weight of binder, 2 to 5 % by weight of glidants, 1 to 5 % of lubricant, 0 to 0.05 % by weight of antioxidant and 0 to 5 % by weight of disintegrant.

In yet another aspect, the present invention provides a pharmaceutical composition of novel amorphous complex of Mirabegron with cyclic oligosaccharides in the molar ratio of 2.5:1 to 4:1 and pharmaceutically acceptable excipients selected from 5 to 50% by weight of polymer, 10 to 30% by weight of filler or diluent, 3 to 12 % by weight of binder, 2 to 5 % by weight of glidants, 1 to 5 % of lubricant, 0 to 0.05 % by weight of antioxidant and 0 to 5 % by weight of disintegrant.

In yet another aspect, the present invention provides a pharmaceutical composition comprises novel amorphous complex Mirabegron with cyclic oligosaccharides in the molar ratio of 2.5:1 to 4:1, 5 to 25% by weight of Polyethylene oxide, 5 to 30% by weight of Polyethylene glycol, 10 to 30% by weight of Lactose, 2 to 8 % by weight of polyvinylpyrrolidone, 2 to 15 % by weight of cellulose polymer, 2 to 5 % by weight of colloidal silicon dioxide, 1 to 5 % of magnesium stearate, 0 to 0.05 % and by weight of butylated hydroxyl toulene and 0 to 5 % by weight of sodium starch glycolate.

Following examples are provided for illustration and should not be considered for limiting the scope of invention.

EXAMPLES
Example 1: Preparation of Mirabegron complex
1. Mirabegron 1.25 Kg was added to a mixture of Methanol 9.900 Litres and Purified water 0.100 Litres under continuous stirring in a vessel.
2. Hydroxy propyl beta cyclodextrin 1.25 Kg was added to a solution of step 1 under continuous stirring.
3. The solution of step 2 was spray dried in spray drier to get the Mirabegron complex.

Example 2: Composition of Mirabegron complex.
Table 1
SR. NO INGREDIENTS Quantity
mg/tablet
1 Mirabegron 50.00
2 Hydroxy propyl beta cyclodextrin 50.00
3 Ethyl Cellulose 10 cps 10.00
4 Butylated Hydroxy Toluene 0.05
5 Methanol Qs
6 Purified water Qs
7 Mirabegron Complex prepared 110.05
8 Lactose Monohydrate 37.00
9 Polyethylene glycol 6000 40.00
10 Polyvinylpyrollidone 7.50
11 Polyethylene oxide WSR 303 20.00
12 Hydroxy Propyl Cellulose 5.45
13 Colloidal anhydrous silica 7.5
14 Magnesium stearate 5.0
15 Opadry yellow 4.50
16 Isopropyl alcohol QS
17 Methylene chloride QS

Manufacturing procedure
1. In a mixture of methanol:water (99:01 ratio), butylated hydroxy toluene, Mirabegron, hydroxy propyl beta cyclodextrin and ethyl celluloses were dissolved under stirring.
2. Spray dried the above prepared solution in spray drier to get the Mirabegron complex.
3. Mirabegron complex, lactose monohydrate, polyethylene glycol 6000 and polyvinylpyrrolidone, polyethylene oxide, hydroxypropyl cellulose, and colloidal anhydrous silica were sifted and loaded in blender.
4. Magnesium stearate was further mixed with step 3.
5. Compressed the lubricated blend to obtain tablet.
6. In a mixture of isopropyl alcohol: methylene chloride mixture (70:30) Opadry yellow dissolved under stirring.
7. Compressed tablets of step 5) were coated with coating solution of step 6)

Example 3: Composition of Mirabegron complex.
Table 2
SR. NO INGREDIENTS Quantity
mg/tablet
1 Lactose Monohydrate 37.00
2 Polyethylene glycol 6000 40.00
3 Polyvinylpyrrolidone 7.50
4 Mirabegron 50.00
5 Hydroxy propyl beta cyclodextrin 50.00
6 Butylated Hydroxy Toluene 0.05
7 Methanol Qs
8 Purified water Qs
9 Polyethylene oxide 20.00
10 Hydroxy Propyl Cellulose 5.45
11 Hydroxy ethyl Cellulose 10.00
12 Colloidal anhydrous silica 7.50
13 Magnesium stearate 5.00
14 Opadry yellow 4.50
15 Isopropyl alcohol QS
16 Methylene chloride QS

Manufacturing procedure
1. Lactose monohydrate, polyethylene glycol 6000 and polyvinylpyrrolidone were sifted and loaded in Fluid Bed Processors.
2. In a mixture of methanol: water (99:01) Butylated hydroxy toluene, Mirabegron and hydroxy propyl beta cyclodextrin were dissolved under stirring.
3. The Mirabegron solution of step 2 sprayed on excipients in step 1.
4. The granulate of step 3 were mixed with polyethylene oxide, hydroxypropyl cellulose, hydroxy ethyl cellulose, and colloidal anhydrous silica in a suitable blender
5. Magnesium stearate was added to a blend prepared in step 4)
6. Compressed the lubricated blend to obtain tablet.
7. In a mixture of isopropyl alcohol: methylene chloride mixture (70:30) Opadry yellow dissolved under stirring.
8. Compressed tablets of step 6) were coated with coating solution of step 7).

Example 4: Composition of Mirabegron complex.
Table 3
SR. NO INGREDIENTS Quantity
mg/tablet
1 Lactose Monohydrate 37.00
2 Polyethylene glycol 6000 40.00
3 Polyvinylpyrrolidone 7.50
4 Mirabegron 50.00
5 Hydroxy propyl beta cyclodextrin 50.00
6 Ethyl Cellulose 10 cps 10.00
7 Butylated Hydroxy Toluene 0.05
8 Methanol Qs
9 Purified water
10 Polyethylene oxide 20.00
11 Hydroxy Propyl Cellulose 5.45
12 Colloidal anhydrous silica 7.5
13 Magnesium stearate 5.0
14 Opadry yellow 4.5
15 Isopropyl alcohol QS
16 Methylene chloride QS

Manufacturing procedure
1. Lactose monohydrate, polyethylene glycol 6000 and polyvinylpyrrolidone were sifted and loaded in Fluid Bed Processors.
2. In a mixture of methanol: water (99:01) butylated hydroxy toluene, Mirabegron, hydroxy propyl beta cyclodextrin and ethyl cellulose were dissolved under stirring.
3. The Mirabegron solution of step 2 sprayed on excipients in step 1.
4. The granulate of step 3 were mixed with polyethylene oxide, hydroxypropyl cellulose, and colloidal anhydrous silica in a suitable blender
5. Magnesium stearate was added to a blend prepared in step 4)
6. Compressed the lubricated blend to obtain tablet.
7. In a mixture of isopropyl alcohol: methylene chloride mixture (70:30) Opadry Yellow dissolved under stirring.
8. Compressed tablets of step 6) were coated with coating solution of step 7).
,CLAIMS:WE CLAIM,
Claim 1: A novel complex of Mirabegron with cyclic oligosaccharides.
Claim 2: The complex according to claim 1, wherein Mirabegron and cyclic oligosaccharides are in the molar ratio of 2.5:1 to 4:1.
Claim 3: The complex according to claim 1, wherein the cyclic oligosaccharides are selected from a group comprising a-cyclodextrins, ß-cyclodextrins, ?-cyclodextrins and their derivatives.
Claim 4: The complex according to claim 1, wherein the cyclic oligosaccharide is hydroxypropyl ß-cyclodextrin.
Claim 5: The complex according to claim 1, wherein the complex is in amorphous form.
Claim 6: A process for the preparation of the novel complex of Mirabegron with cyclic oligosaccharides, comprising;
a) mixing Mirabegron & cyclic oligosaccharides in molar ratio of 2.5:1 to 4:1 in a solvent to get clear solution;
b) isolating the complex by removal of the solvent from the solution;
c) optionally, mixing of isolated complex with suitable pharmaceutically acceptable excipients.
Claim 7: The process according to claim 6, wherein the pharmaceutically acceptable excipients are selected from a group comprising binders, diluents, lubricants, glidants, disintegrants, antioxidants and polymers.
Claim 8: A pharmaceutical composition comprising novel complex of Mirabegron with cyclic oligosaccharides and pharmaceutically acceptable excipients.
Claim 9: The pharmaceutical composition according to claim 8, wherein the pharmaceutically acceptable excipients comprising 5 to 25% by weight of Polyethylene oxide, 5 to 30% by weight of Polyethylene glycol, 10 to 30% by weight of Lactose, 2 to 8 % by weight of Polyvinylpyrrolidone, 2 to 15 % by weight of cellulose polymer, 2 to 5 % by weight of Colloidal silicon dioxide, 1 to 5 % of Magnesium stearate, 0 to 0.05 % and by weight of Butylated hydroxyl toulene and 0 to 5 % by weight of Sodium starch glycolate.

Claim 10: A process for preparation of the pharmaceutical composition of claim 8, comprising;
a) dispensing of the excipients in fluid bed processor;
b) dissolving Mirabegron and suitable cyclic oligosaccharides in suitable solvent under stirring to get clear solution;
c) granulating excipients in step a) with solution of step b) in Fluid Bed Processor;
d) lubricating the granules of step c);
e) granulates of step d) can be further compressed to tablet or filled in a capsule;
f) optionally tablet can be coated with suitable coating agent.