"A PHARMACEUTICAL COMPOSITION COMPRISING BREXPIPRAZOLE"
TECHNICAL FIELD OF THE INVENTION:
The present invention relates to an immediate release tablet core composition comprising Brexpiprazole or its pharmaceutically acceptable salts and carriers. The present invention is also relates to a pharmaceutical formulation which contains Brexpiprazole having good storage stability.
BACKGROUND OF THE INVENTION:
Brexpiprazole an atypical antipsychotic, It is a dopamine D2 receptor partial agonist and has been described as a "serotonin-dopamine activity modulator" (SDAM). The mechanism of action of Brexpiprazole in the treatment of major depressive disorder (or) schizophrenia is
unknown. However, the efficacy of Brexpiprazole may be mediated through a combination of partial agonist activity at serotonin 5-HT1A and dopamine D2 receptors, and antagonist activity at serotonin 5-HT2A receptors.
The drug was developed by Otsuka Pharmaceutical Co., Ltd. Brexpiprazole Tablet (REXULTI®) is approved in USA on July 10, 2015 for treatment of adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD) and schizophrenia.
Brexpiprazole is chemically known as 7-{4-[4-(l-Benzothiophen-4-yl) piperazin-1-yl] butoxy} quinolin-2(lH)-one. Brexpiprazole is non hygroscopic, with white to off-white crystals (or) crystalline powders, and a melting point of 183°C (decomposition). It is practically insoluble in water.The molecular formula is C25H27N3O2S and its molecular weight is 433.57. The chemical structure of Brexpiprazole is shown as below:

Brexpiprazole tablets are for oral administration and available in 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg and 4 mg strengths. REXULTI® tablets contain Lactose monohydrate, corn starch, microcrystalline cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, magnesium stearate, hypromellose, and talc. Colorants include titanium dioxide, iron oxide and ferrosferric oxide.
WO2013054872 discloses Brexpiprazole tablet composition comprising an excipient, a binder, a disintegrant, and a lubricant , wherein the excipient is at least one member selected from the group consisting of lactose, corn starch, and microcrystalline cellulose; the binder is hydroxypropyl cellulose; the disintegrant is at least one member selected from the group consisting of low-substituted hydroxypropyl cellulose, croscarmellose sodium, and sodium carboxymethyl starch; and the lubricant is magnesium stearate and method of preparation thereof. Further he disclosed tablet tends to have reduced photo stability and storage stability problems and the solubility of Brexpiprazole in water is itself 0.0020 mg/ml, the use of hydroxyl propyl cellulose (HPC) reduce stability of the product.
Indian patent application IN 201611038602 relates to pharmaceutical composition of brexpiprazole and process for preparation thereof. Wherein the composition is substantially free of binder and/or disintegrant, colorant and photostabilisers. Composition is prepared particularly used dry process for the preparation. However, dry process often produces a high percentage of fine granules, which can compromise the quality or create yield problems for the product.
Indian patent application IN 201721002429 discloses pharmaceutical compositions of brexpiprazole tablet comprising binder (povidone or crospovidone) and stabilizer (EDTA salts and ascorbic acid or its derivatives) and method of preparation thereof. Wherein povidone or crospovidone was used as a binder, the obtained tablet tends to have reduced photo stability and storage stability.
WO 2018033481 (hereinafter uses '481) discloses immediate release tablet comprising 20% brexpiprazole and at least one pharmaceutically acceptable excipient, wherein the tablet is made by direct compression.

In order to solve the above problems, the present inventors has developed a composition with provide stable product as well as improved drug bioavailability. Moreover inventors here using simple method in comparison to above said methods, which is process friendly in commercial aspects to get a good yield with following advantages
• Hypromellose (Methocel E3 premium) can dissolve in binder solvent to use as wet binder.
• Consistent granules shall manufactured with Hypromellose.
• Less probability of batch to batch variation.
• It is easy to extract the drug from HPMC granules when compared to HPC granules.
SUMMARY OF THE INVENTION:
The present invention relates to a pharmaceutical solid dosage form comprising a Brexpiprazole as an active ingredient or a pharmaceutically acceptable salt thereof and a binder, a process for the preparing the pharmaceutical stable solid dosage form.
Accordingly, the main object of the present invention provides a pharmaceutical composition comprising Brexpiprazole having good storage stability.
Another object of the present invention provides pharmaceutical composition comprising brexpiprazole or a salt thereof as an active ingredient with a binder especially HPMC (hydroxy propyl methyl cellulose), further comprising a diluent/filler, a disintegrant and a lubricant.
The present invention is to provide a solid oral dosage form or an immediate release tablet comprising Brexpiprazole or a salt thereof and pharmaceutical acceptable excipients thereof and tablet dosage form is prepared by wet granulation technique process comprising the following steps of.

A solid oral pharmaceutical composition comprising Brexpiprazole or a salt thereof and pharmaceutical acceptable excipient, wherein process for the preparation of composition as follows;
i. Sifting of brexpiprazole and intragranular excipients (a diluent/filler, a disintegrant) on dry mixing,
ii. Preparing binder solution by using hydroxyl propyl methyl cellulose (HPMC) with aqueous solvent,
iii. Granulate the step (i) with step (ii) to attain desired granules,
iv. Granules obtain in step(iii) is blending with extra granular materials by using disintegrate and followed by lubrication, and
v. Finally compression and film coating with opadry.
Wherein, tablet dosage form consisting following excipients.
i. The intragranular excipients are Lactose monohydrate, microcrystalline cellulose 101, low substituted HPC (hydroxyl propyl cellulose);
ii. Binder is hydroxyl propyl methyl cellulose (HPMC);
iii. Extra granular materials are low substituted HPC (hydroxyl propyl cellulose) and magnesium stearate.
iv. Film coating comprising Opadry.

DETAILED DESCRIPTION OF THE INVENTION:
The present invention provides a pharmaceutical composition comprising Brexpiprazole having good storage stability of the tablet.
The object of the present invention provides pharmaceutical composition comprising brexpiprazole or a salt thereof as an active ingredient with a binder especially HPMC (hydroxy propyl methyl cellulose), further comprising a diluent/filler, a disintegrant and a lubricant.
The term "composition" or "pharmaceutical composition" or "solid dosage form" as used herein synonymously include solid dosage forms such as granules, multiunit particulate systems (MUPS), pellets, spheres, tablets, capsules, mini-tablets, beads, particles and the like.
The term 'excipient' means a pharmacologically inactive component such as diluent, disintegrant, carrier, filler, lubricant, binder, and solvent, coating agent or the like. These are generally safe, nontoxic. Reference to an excipient includes both one and more than one such excipient.
The term 'stable' refers to formulations that substantially retain the label amount of the therapeutically active ingredient during storage for commercially relevant times, and the drug-related impurity contents in the formulations remain within acceptable limits. Further, the term 'stable' also optionally refers to formulations that contain polymorphically stable active ingredient.
As used herein, the term 'active ingredient' includes any compound or therapeutic agent known to or that demonstrates advantageous properties when administered to a patient in need of treatment for the corresponding disease state. The most preferred active ingredient is Brexpiprazole.

As used herein, the term 'therapeutically effective amount' means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, lessening in severity or amelioration of disease.
As used herein, the term 'treating' or 'treatment' refers to the prophylaxis, mitigation, prevention, amelioration, or suppression of a disorder modulated by Brexpiprazole in a mammal.
Throughout this specification and the appended claims, it is to be understood that the words "comprise", "have", "contain" and "include" and variations such a "comprises", "comprising", "having", "containing" "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
As used herein, the term 'immediate release' refers to a part or layer or all of a dosage form that releases active agent substantially immediately upon contact with gastric environment and that results in substantially complete dissolution within about 1 hour. When used in association with the dissolution profiles discussed herein, the term 'immediate release' refers to that portion of a dosage form according to the present invention that delivers active agent over a period of time less than 1 hour.
As used herein, the term 'wet granulation' refers to any process comprising the steps of addition of a liquid to powdered materials, agitation, and drying to yield a solid dosage form. The resulting granulated drug product may be further processed into various final dosage forms.
As used herein, the term 'dissolution' refers to the process by which the active ingredient is being dissolved from the dosage form in the presence of a solvent. In the present invention dissolution is carried out in 900 ml of pH 4.3 Acetate buffer (0.05 M) as dissolution medium in a Paddle (Type II) apparatus at 50 RPM.
As used herein, the term 'stability' refers to any preparation of Brexpiprazole having sufficient physical and chemical stability to allow storage at a convenient temperature and

humidity, for a commercially reasonable period. In the present invention stability is carried out at 40°C/75%RH and 25°C/ 60% RH for a period of one month, two months, three months, six months, nine months, twelve months thereof.
As used herein, the term 'core' refers to the solid pharmaceutical composition wherein Brexpiprazole is present in the core is an immediate release and without coating of the tablet.
Diluents/fillers includes, but are not limited to, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, starch, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, dextrates, dextrin, dextrose, kaolin, magnesium carbonate, magnesium oxide, sugars such as sucrose; sugar alcohols such as mannitol, sorbitol, erythritol; and mixtures thereof.
Binders includes, but are not limited to, binder is hydroxypropyl methylcellulose E5, hydroxypropyl methylcellulose E3 LV, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxy ethyl cellulose, Povidone, hydroxypropyl cellulose, carbomers, carboxymethylcellulose sodium, dextrin, shellac, zein, gelatin, polymethacrylates, polyvinyl pyrrolidone, or combinations thereof.
Disintegrant includes, but are not limited to, Low substituted HPC (hydroxy propyl cellulose), croscarmellose sodium, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, sodium alginate and mixtures thereof.
Lubricant includes, but are not limited to, anti-tacking agent, sodium lauryl sulphate, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glycerylpalmitostearate, glyceryl behenate, polyethylene glycols, corn starch, sodium stearylfumarate, sodium benzoate, mineral oil, and mixtures thereof;
Solvents includes, but are not limited to acetone, isopropyl alcohol and purified water.
In one embodiment, the present invention provides a pharmaceutical solid dosage form
rnmnrisincr hrexninraznle and a hinder esneriallv hvdrrorv nrnnvl methvl rellnlnse fHPMC!^

providing good storage stability and bioavailability of the solid dosage form when comparatively HPC binder.
In another embodiment, the present invention is to provide a solid oral dosage form or an immediate release tablet comprising Brexpiprazole or a salt thereof and pharmaceutical acceptable excipients thereof and tablet dosage form is prepared by wet granulation technique process comprising the following steps of.
A solid oral pharmaceutical composition comprising Brexpiprazole or a salt thereof and pharmaceutical acceptable excipient, wherein process for the preparation of composition as follows;
i. Sifting of brexpiprazole and intragranular excipients (a diluent/filler, a disintegrant) on dry mixing,
ii. Preparing binder solution by using hydroxyl propyl methyl cellulose (HPMC) with aqueous solvent,
iii. Granulate the step (i) with step (ii) to attain desired granules,
iv. Granules obtain in step(iii) is blending with extra granular materials by using disintegrate and followed by lubrication, and
v. Finally compression and film coating with opadry.
In yet another embodiment, tablet dosage form consisting following excipients.
i. The intragranular excipients are Lactose monohydrate, microcrystalline cellulose 101, low substituted HPC (hydroxyl propyl cellulose);
ii. Binder is hydroxyl propyl methyl cellulose (HPMC);
iii. Extra granular materials are low substituted HPC (hydroxyl propyl cellulose) and magnesium stearate.
iv. Film coating comprising Opadry.

In most preferred embodiment, the present invention provides a solid oral pharmaceutical composition comprising brexpiprazole or a salt thereof as an active ingredient in the form of a tablet may be an uncoated tablet having no coating layer applied thereon or a coated tablet having a coating layer on the surface thereof.
In another embodiment, the present invention comprising brexpiprazole for immediate release for oral administration and it can be in the form of tablet or capsule. Preferably, said composition is in the form of tablet for oral administration.
In another embodiment, the present invention provides following advantages...
• Hypromellose can dissolve in binder solvent to use as wet binder.
• Consistent granules shall manufactured with Hypromellose.
• Less probability of batch to batch variation.
• It is easy to extract the drug from HPMC granules when compared to HPC granules.
In another embodiment of the present invention, the method for producing the tablet of the present invention is not particularly limited; for examples of the tablet forming methods include tableting, such as direct compression tableting, dry tableting, wet tableting, and external lubrication tableting. More preferably using wet granulation of the Brexpiprazole tablets.
In further embodiment of the present invention, method of using the solid dosage form of Brexpiprazole or salts thereof in the treatment of psychotic disorder like adjunctive treatment of major depressive disorder (MDD) and Schizophrenia.
In further embodiment coating comprising Opadry and purified water, wherein Opadry comprising polymer, plasticizer and pigment.

The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

Manufacturing Process:
1. Sifting: Co-Sift Brexpiprazole with Microcrystalline Cellulose, Lactose monohydrate, maize starch , and L-HPC through 30 # mesh.
2. Binder preparation: Dissolve required quantity of Purified water, to this add weighed quantity of hypromellose under stirring and continue stirring upto clear solution was formed.

3. Granulation: Granulate the step 1 with step 2 to attain desired granules and dried the wet granules to attain desired % LOD @ 105°C and mill with 1.0 mm screen until all the dried granules passes through 30# mesh.
4. Extragranular: Sift L-HPC through 30# mesh and blend with step 3 in a suitable blender.
5. Sift Magnesium stearate through 60 # mesh.
6. Lubrication: Blend the step 5 and step no.4 materials for 15 mins.
7. Compression: Compress the above blend by using suitable tooling for all strength.
8. Film Coating :Disssolve opradry (HPMC based coating materials ) in reqired quanity of water under stirring till dispersion formed and coat the core tablets using coating solution.
In-Vitro Dissolution Study:
Dissolution test were performed using USP apparatus type-II (paddle) apparatus at a rotation speed of 50 rpm with 900 ml of acetate buffer (pH-4.3) as dissolution medium at 37±0.5°C. Not less than 45 % release was obtained in 30 minutes.

We Claim:
1. A solid oral pharmaceutical composition comprising Brexpiprazole or a salt thereof and
pharmaceutical acceptable excipient, wherein process for the preparation of composition
as follows;
i. Sifting of brexpiprazole and intragranular excipients (a diluent/filler, a disintegrant) on dry mixing,
ii. Preparing binder solution by using hydroxyl propyl methyl cellulose (HPMC) with aqueous solvent,
iii. Granulate the step (i) with step (ii) to attain desired granules,
iv. Granules obtain in step(iii) is blending with extra granular materials by using disintegrate and followed by lubrication, and
v. Finally compression and film coating with opadry.
2. The pharmaceutical composition as claimed in claim 1, a compressed Tablet which
comprising:

3. The pharmaceutical composition as claimed in claim 1, wherein pharmaceutical composition comprising brexpiprazole or a salt thereof as an active ingredient, binder diluent/filler, a disintegrant and a lubricant.
4. The pharmaceutical composition as claimed in claim 2, wherein tablet comprising excipients weight is based on the core composition.
5. The pharmaceutical composition as claimed in claim 1, wherein, tablet is an uncoated tablet comprising intragranular and extra granular excipients.
6. The pharmaceutical composition as claimed in claim 1, wherein intragranular ingredients comprising lactose monohydrate, micro crystalline cellulose, maize starch and low substituted HPC; extra granular ingredients comprising low substituted HPC and magnesium stearate; binder is Hypromellose (HPMC).
7. The pharmaceutical composition as claimed in claim 1, wherein solid dosage form is tablet is prepared by wet granulation method.
8. The pharmaceutical composition as claimed in claim 1, wherein Brexpiprazole tablet is used for the treatment of psychotic disorder like adjunctive treatment of major depressive disorder (MDD) and Schizophrenia.