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Pharmaceutical Composition Of Brexpiprazole And Process For Preparation Thereof

Abstract: The present invention relates to a solid oral pharmaceutical composition comprising antipsychotic drug like Brexpiprazole or itspharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof and a process for its preparation. The prior art discloses technical challenges such as photosensitivity and low solubility of Brexpiprazole and low storage stability of the composition. The present invention provides a solid oral pharmaceutical composition of Brexpiprazole with desirable formulation attributes such as thickness, hardness, and dissolution and storage stability.

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Patent Information

Application #
Filing Date
11 November 2016
Publication Number
20/2018
Publication Type
INA
Invention Field
CHEMICAL
Status
Email
Parent Application

Applicants

JUBILANT GENERICS LIMITED
PLOT 1 A, SECTOR-16A, NOIDA, UTTAR PRADESH-201301, INDIA

Inventors

1. KUMAR, DINESH
D-12, SECTOR-59, NOIDA, UTTAR PRADESH-201301, INDIA
2. MEHTA, KAMAL S.
D-12, SECTOR-59, NOIDA, UTTAR PRADESH-201301, INDIA

Specification

FIELD OF THE INVENTION This invention in general relates to pharmaceutical composition comprising D2 dopamine partial agonist or its pharmaceutical^ acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof. In particular, the present invention proposes a solid oral pharmaceutical composition comprising atypical antipsychotic and process for preparing the same. BACKGROUND OF THE INVENTION Antipsychotic drugs in general are known as major tranquilisers and neuroleptics and are used to treat psychiatric conditions. Brexpiprazole is an atypical antipsychotic drug which acts as a dopamine D2 receptor partial agonist, a serotonin 5-HT2A receptor antagonist, an a-adrenergic receptor antagonist, as well as a serotonin uptake inhibitor (or a serotonin reuptake inhibitor). It possesses a wide therapeutic spectrum in the treatment of central nervous system diseases like adjunctive 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. It is represented by the following formula: Brexpiprazole tablet was approved in the USA under trade name REXULTI® on Jul 10, 2015. It is available in 0.25, 0.5, 1, 2, 3 and 4 mg strengths. REXULTI® tablets contain lactose monohydrate, corn starch, microcrystalline cellulose, hydroxypropyl cellulose, lowsubstituted hydroxypropyl cellulose, magnesium stearate, hypromellose, and talc. Colorants include titanium dioxide, iron oxide and ferrosferric oxide. 2 LHI 10-11-2817- 11:4 5- U.S. Patent Nos. 7,888,362, 8,349,840 and 8,618,109 are assigned to Otsuka and cover Brexpiprazole as a product. U.S. Publication Nos. 20160158227 and 20140234417 are assigned to Otsuka and disclose a method for producing Brexpiprazole tablet. The method comprises the steps of: granulating a mixture containing Brexpiprazole, an excipient (lactose, corn starch, and microcrystalline cellulose), a binder (hydroxypropyl cellulose), and a disintegrant (low-substituted hydroxypropyl cellulose, croscarmellose sodium, and sodium carboxymethyl starch), and further mixing thereto a lubricant (magnesium stearate); and forming the obtained mixture into a tablet. These publications disclose that when polyethylene glycol (macrogol) is present in the coating layer, the obtained tablet tends to have reduced photostability and storage stability. Further, the presence of povidone and crospovidone in the tablet leads to reduced photostability and storage stability. It was observed that higher photostability can be attained by applying a coating layer containing a colorant to the tablet core. Brexiprazole is a BCS Class II drug with low solubility and high permeability and is a photounstable compound and poses technical challenges in the formulation development. The present invention relates to a simple, reproducible, and cost-effective process for preparing pharmaceutical formulation of Brexpiprazole and its pharmaceutically acceptable salt thereof. Further, pharmaceutical compositions prepared according to the manufacturing process of the present invention exhibits desirable technical attributes such as dissolution, thickness, hardness and disintegration time. SUMMARY OF THE INVENTION One embodiment of the present invention relates to a solid oral pharmaceutical composition comprises a pharmaceutically effective amount of the D2 dopamine partial agonist, preferably Brexpiprazole or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof present in an amount of from about 0.01% to about 40% by weight of the total weight of the uncoated composition, 3 LHI- 18-11 -2017 11 : 45- wherein the composition exhibits technical attributes such as hardness, thickness, distintegration time and dissolution and a process for preparing the same. In yet another embodiment of the invention, the solid oral pharmaceutical composition comprises from about 0.05 mg to about 25 mg of Brexpiprazole or its pharmaceutical^ acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof. Another embodiment of the present invention encompasses a solid oral pharmaceutical composition comprises from about 0.01 % to about 40% Brexpiprazole or its pharmaceutical^ acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof by weight of the uncoated composition and a pharmaceutical^ acceptable excipient selected from at least one of diluent, binder, disintegrant, surfactant, alkaline agent, glidant and other pharmaceutical excipients. Combination of excipients performing the same function may also be used to achieve desired formulation characteristics. In another embodiment, the present invention includes a solid oral pharmaceutical composition comprises Brexpiprazole or its pharmaceutical^ acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, wherein the polymorphic form of Brexpiprazole remains substantially unchanged. In another embodiment, the present invention includes a solid oral pharmaceutical composition comprises Brexpiprazole or its pharmaceutical^ acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, wherein the composition is substantially free of dihydrate form. In another embodiment, the present invention includes a solid oral pharmaceutical composition comprises Brexpiprazole or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof wherein, the composition is substantially free of other polymorphic forms when measured using powder X-ray diffraction method performed on a Bruker D8 Advance powder X-ray diffractometer using Cu Ka radiation (1.546 A); 20 angles are recorded with an experimental error of ±0.2°. In another embodiment of the present invention, the solid oral pharmaceutical composition of the invention is prepared by wet or dry process. The wet and dry 4 1O- 1 1 - 2 0 1 7 1 1 : 45 processes include, but are not limited to. wet granulation, dry granulation, dry blending, direct compression, extrusion and spheronization. Other formulation techniques are also contemplated within the scope of the present invention. In particular, dry process such as dry granulation and direct compression are used. In another embodiment of the present invention, the solid oral pharmaceutical composition comprises Brexpiprazole or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, wherein the composition is substantially free of binder. In another embodiment of the present invention, the solid oral pharmaceutical composition comprises Brexpiprazole or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, wherein the composition comprises binder in an amount less than about 0.1% by weight of the uncoated composition. In another embodiment of the present invention, the solid oral pharmaceutical composition comprises Brexpiprazole or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, wherein the composition is substantially free of disintegrant. In another embodiment of the present invention, the solid oral pharmaceutical composition comprises Brexpiprazole or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, wherein the composition comprises disintegrant in an amount less than about 1% by weight of the uncoated composition. In another embodiment of the present invention, the solid oral pharmaceutical composition comprises Brexpiprazole or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, wherein the composition comprises crospovidone in an amount of from about 0% to about 10% by weight of the uncoated composition. In another embodiment of the present invention, the solid oral pharmaceutical composition comprises Brexpiprazole or its pharmaceutically acceptable salts, esters, 5 solvates, polymorphs, enantiomers or mixtures thereof, wherein the composition is substantially free of binder and/or disintegrant. In another embodiment of the present invention, the solid oral pharmaceutical composition comprises Brexpiprazole or its pharmaceutical^ acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof and a pharmaceutical ly acceptable excipient, wherein the composition is free of hydroxypropyl cellulose as a binder and/or low substituted hydroxypropyl cellulose as a disintegrant. In another embodiment of the present invention, the solid oral pharmaceutical composition comprises Brexpiprazole or its pharmaceutical ly acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, wherein the composition comprises binder in an amount less than about 0.1% and/or disintegrant in an amount less than about 1% by weight of the uncoated composition. In yet another embodiment of the present invention, the solid oral pharmaceutical composition comprises Brexpiprazole or its pharmaceutical^ acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, wherein the composition comprises photostabilizers in an uncoated composition. In yet another embodiment of the present invention, the solid oral pharmaceutical composition comprises Brexpiprazole or its pharmaceutical^ acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, wherein the composition comprises photostabilizers in amount of from about 0% to about 1% by weight of the uncoated composition. In yet another embodiment of the present invention, the solid oral pharmaceutical composition comprises Brexpiprazole or its pharmaceutical^ acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, wherein the composition comprises binder in an amount of from about 0% to about 5% by weight of the uncoated composition. In another embodiment of the present invention, the solid oral pharmaceutical composition comprises Brexpiprazole or its pharmaceutical ly acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, wherein the composition is substantially free of colorants. 6 L H I 1 0 - 1 1 - 2 0 1 7 11 : 4 5 In another embodiment of the present invention, the solid oral pharmaceutical composition comprises Brexpiprazole or its pharmaceutical ly acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof wherein the composition comprises colorants in an amount less than about 0.1% by weight of the uncoated composition. In another embodiment of the present invention, the solid oral pharmaceutical composition comprises Brexpiprazole or its pharmaceutical^ acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, wherein the composition is free of microcrystalline cellulose, lactose, and corn starch. In yet another embodiment of the present invention, the solid oral pharmaceutical composition comprises Brexpiprazole or its pharmaceutical^ acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, wherein the composition comprises diluent selected from the group comprising mannitol, calcium phosphate, dibasic anhydrous, calcium phosphate, dibasic dihydrate, calcium phosphate tribasic, calcium sulphate, cellulose powdered, cellulose acetate, compressible sugar, confectioner's sugar, dextrates, dextrose, fructose, lactitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, polydextrose, sodium alginate, sorbitol, sucrose, trehalose and xylitol, or mixtures thereof. In another embodiment, the solid oral pharmaceutical composition comprising Brexpiprazole or its pharmaceutical ly acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof of the present invention includes particle size of Brexpiprazole or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof of, wherein D90 is less than about 200 ^m. Another embodiment of the present invention relates to a pharmaceutical composition of an atypical antipsychotic preferably D2 dopamine partial agonist, wherein said composition comprises a core and a coating layer over the core. In another embodiment, the solid oral pharmaceutical composition comprises Brexpiprazole or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof and a pharmaceutically acceptable excipient, wherein the composition comprises a core comprising Brexpiprazole and a coating layer over 7 I 18-11-2817 11:4 5 the core, and wherein the coating layer comprises a polymer selected from the group comprising polyvinyl alcohol, polyvinyl pyrrolidone or polyethylene glycol. Another embodiment of the present invention provides a process for the preparation of a solid oral pharmaceutical composition comprising Brexpiprazole or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof, wherein the process comprises: a) mixing Brexpiprazole optionally with at least one binder and/or disintegrant; b) compacting the mixture of step a); c) optionally milling the compacts of step b) using suitable screen; d) lubricating the milled material of step c) with lubricant; e) compressing the lubricated blend of step d) into tablets with a suitable tooling; and f) optionally coating the tablets of step e). Another embodiment of the present invention provides a process for the preparation of a solid oral pharmaceutical composition comprising Brexpiprazole or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof, wherein the process comprises: a) mixing Brexpiprazole optionally with at least one binder and/or disintegrant; b) lubricating the mixture of step a) with a lubricant; c) compressing the lubricated blend of step b) into tablets with a suitable tooling; and d) optionally coating the tablets of step c). Another embodiment of the present invention provides a process for the preparation of a solid oral pharmaceutical composition comprising Brexpiprazole or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof of, comprising the steps of: (a) dry blending drug and excipients; (b) wet granulation (aqueous or non-aqueous) of the blend to obtain granules; (c) drying the granules in drier; (d) milling and screening the dry granules to obtain granules; (e) 8 L H I 1 0 - 1 1 - 2 0 1 7 1 1 : 45 lubricating the dried granules of step d; (f) optionally compressing the lubricated granules to tablets or filling into capsules, and (g) optionally, coating of compressed tablets of step (f). Another embodiment of the present invention provides a process for the preparation of a solid oral pharmaceutical composition comprising Brexpiprazole or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof of, comprising the steps of: (a) dry blending drug and excipients; (b) dry granulation (roller compaction or slugging) of the blend to obtain briquettes or slug; (c) milling and screening the granules to obtain desired size; (d) lubricating the granules of step c; (e) optionally compressing the lubricated granules to tablets or filling into capsules; and (f) optionally, coating of compressed tablets of step (e). Another embodiment of the present invention provides a process for the preparation of a solid oral pharmaceutical composition comprising Brexpiprazole or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof of, comprising the steps of: (a) dry blending of drug and directly compressible excipients; (b) optionally compressing the blend into tablets or filling into capsules; and (c) optionally, coating of compressed tablets of step (b). In another embodiment of the present invention, the granules used in the pharmaceutical composition comprising Brexpiprazole or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof have acceptable bulk density. In yet another embodiment of the present invention, the granules used in the pharmaceutical composition comprising Brexpiprazole or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof have acceptable tapped density. In another embodiment of the present invention, the granules used in the pharmaceutical composition comprising Brexpiprazole or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof have and average diameter of about 0.5 to about 2 mm. LBI 1811- 817 11: 9 In another embodiment, the solid oral pharmaceutical composition comprising Brexpiprazole or its pharmaceutical^ acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof is stable at 40°C and 75% relative humidity for a period of at least three months. The solid oral pharmaceutical composition exhibits acceptable storage stability and photostability along with other pharmaceutical^ acceptable attributes. In further embodiment, the present invention includes method of using the coated solid oral pharmaceutical composition comprising core of Brexpiprazole or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof in the treatment of psychotic disorder like adjunctive treatment of major depressive disorder (MDD) and schizophrenia. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows the overlay X-ray powder diffraction pattern of Brexpirazole API, Placebos 1, 2 and 3, and Tablets of Examples I, 2 and 3. DESCRIPTION OF THE INVENTION The present invention can be more readily understood by reading the following detailed description of the invention and study of the included examples. As used herein, the term "composition", as in pharmaceutical composition, is intended to encompass a drug product comprising Brexpiprazole or its pharmaceutical ly acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, and the other inert ingredient(s) (pharmaceutical^ acceptable excipients). Such pharmaceutical compositions are synonymous with "formulation" and "dosage form". Pharmaceutical composition of the invention include, but is not limited to, tablets, capsules, granules, pellets, beads, minitabs, spherules, beadlets, microcapsules, millispheres, microspheres, sachets, and the like. Preferably, the pharmaceutical composition refers to tablets. 10 LHI 1G-II- 201? 11:45 "Atypical antipsychotics" as used herein refers to antipsychotic compounds of therapeutic interest whose half-life is more than 70 hours for example Aripiprazole, Brexpiprazole and the like. "Brexpiprazole" as used herein refers to the free acid form, its salts, esters, solvates, polymorphs, enantiomers or mixtures thereof. The term "excipient" means a pharmacologically inactive component such as a diluent, lubricant, disintegrant, binder, surfactant, carrier, or the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for veterinary as well as human pharmaceutical use. Reference to an excipient includes both one and more than one such excipient. Co-processed excipients are also covered under the scope of present invention. Further, excipient may be in the form of powders or in the form of dispersion. Combination of excipients performing the same function may also be used to achieve desired formulation characteristics. As used in this specification, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to "a process" includes one or more process, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth. Unless otherwise stated the weight percentages expressed herein are based on the final weight of the composition or formulation. "Bulk density" as used herein, refers to the ratio of the mass of an untapped powder sample and its volume including the contribution of the interparticulate void volume. Bulk density indicates mass of a powder material that can be filled in per unit volume. "Tapped density" as used herein, refers to the ratio of the mass of a tapped powder sample and its volume. Tapped density of granules is determined using Electrolab tap density tester. As used herein, the term "about" means ± approximately 20% of the indicated value, such that "about 10 percent" indicates approximately 08 to 12 percent. "Substantially free of binder" as used herein, refers to the solid pharmaceutical composition of brexpiprazole or its pharmaceutical ly acceptable salts, esters, solvates, 11 L H I 1 0 - 1 1 - 2 0 1 7 1 1 : 45 polymorphs, enantiomers or mixtures thereof, which contains less than 1% binder by weight of the uncoated composition. More particularly, it refers to the solid pharmaceutical composition of brexpiprazole or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof which does not contain a binder. "Substantially free of disintegrant" as used herein, refers to the solid pharmaceutical composition of brexpiprazole or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, which contains less than 2% disintegrant by weight of the of the uncoated composition. More particularly, it refers to the solid pharmaceutical composition of brexpiprazole or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof which does not contain a disintegrant. "Substantially free of colorant" as used herein, refers to the solid pharmaceutical composition of brexpiprazole or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof which does not contain a colorant in the coating layer. "Core" as used herein, refers to the solid pharmaceutical composition wherein brexpiprazole is present in the matrix structure with other pharmaceutically acceptable excipients. Particularly, the core is an immediate release core. "Uncoated composition" as used herein, refers to the solid pharmaceutical composition wherein core is devoid of coating "Coated composition" as used herein, refers to the uncoated composition wherein core is coated by a coating. Particularly, the coating is an immediate release film coating. "" as used herein means refers to chemical stability, wherein not more than 5% w/w of total related substances are formed on storage at 40°C and 75% relative humidity (R.H.) or at 25°C and 60% R.H. for a period of at least three months. "Low-substituted hydroxypropyl cellulose" is a derivative of cellulose including hydroxypropoxyl groups by about 5 to 16%. "Hydroxypropyl cellulose" is a derivative of cellulose including hydroxypropoxyl groups by about 50 to 85%. 12 L H I 1 0 - 1 1 - 2 0 1 7 1 1 - 45 In another embodiment the solid oral pharmaceutical composition of the present invention includes particle size of Brexpiprazole or its pharmaceutical^ acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, wherein D90 is less than about 200 jam. Particularly, D90 is in the range from about 10 ^m to about 200 \xm. More particularly, D90 is in the range from about 20 \xm to about 150 ^xm. In another embodiment the present invention includes particle size of free drug particulate form of Brexpiprazole or its pharmaceutical^ acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, wherein particle diameter at 90% cumulative volume is less than about 100 urn. Particle diameter at X% cumulative volume is a method of designating volume-based particle size distribution such that X% by volume of the particles have diameter equal to less than the stated value. Particle size reduction can be performed by techniques including but not limited to fluid energy milling, ball milling, colloid milling, roller milling, hammer milling and the like. Particle size and particle size distribution can be measured by techniques such as Laser light scattering (e.g. Malvern Light Scattering), Coulter counter, microscopy and the like. In another embodiment, the present invention includes a solid oral pharmaceutical composition comprising from about 0.01% to about 40% by weight of Brexpiprazole or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof based on the total weight of the uncoated composition, wherein the composition is substantially free of other polymorphic forms when measured using powder X-ray diffraction method performed on a Bruker D8 Advance powder X-ray diffractometer using Cu K / Jt JL 18 Colorants include but are not limited to iron oxides such as red ferric oxide, yellow ferric oxide, and black iron oxide; titanium oxide; beta-carotene; food blue No. 2 and food blue No. 2 Aluminium Lake. Various film forming agents include but are not limited to cellulose derivatives such as soluble alkyl- or hydroalkylcellulose derivatives such as methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxymethyl ethylcellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, etc., acidic cellulose derivatives such as cellulose acetate phthalate, cellulose acetate trimellitate, and methylhydroxypropylcellulose phthalate, polyvinyl acetate phthalate, etc., insoluble cellulose derivative such as ethylcellulose and the like, dextrins, starches and starch derivatives, polymers based on carbohydrates and derivatives thereof, natural gums such as gum arabic, xanthans, alginates, polyacrylic acid, polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone, polymethacrylates and derivatives thereof (Eudragit™), chitosan and derivatives thereof, shellac and derivatives thereof, waxes and fat substances. In another embodiment of the present invention, the solid oral pharmaceutical composition comprises Brexpiprazole or its pharmaceutical^ acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, wherein, the composition is substantially free of colorants. In another embodiment of the present invention, the solid oral pharmaceutical composition comprises Brexpiprazole or its pharmaceutical^ acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures, thereof wherein the composition comprises colorants in an amount less than about 0.1% by weight of the uncoated composition. In another embodiment, the solid oral pharmaceutical composition comprises Brexpiprazole or its pharmaceutical^ acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof and a pharmaceutical ly acceptable excipient, wherein the composition comprises a core comprising Brexpiprazole and a coating layer over the core, and wherein the coating layer comprises a polymer selected from the group comprising polyvinyl alcohol, polyvinyl pyrrolidone or polyethylene glycol. 19 In another embodiment, the Brexpiprazole tablets of the present invention comprise of a core comprising about 0.01% to about 40% by weight of Brexpiprazole or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof; at least one diluent present in an amount of from about 10% to about 90% by weight; at least one disintegrant present in an amount of from about 1% to about 25%) by weight; at least one binder present in an amount of less than about 0.5% by weight; a coating layer on the core in an amount of about 2% to about 5% by weight of the uncoated tablet core. In another embodiment, the Brexpiprazole tablets of the present invention comprise a core comprising about 0.01% to about 40% by weight of Brexpiprazole or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof; at least one diluent present in an amount of from about 10% to about 90% by weight; at least one disintegrant present in an amount of from about 1% to about 25%) by weight; a coat on the core in an amount of about 3% to about 4% by weight of the uncoated tablet core, wherein the composition is devoid of binder. In another embodiment, the Brexpiprazole tablets of the present invention comprise a core comprising about 0.01%) to about 40% by weight of Brexpiprazole or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof; at least one diluent present in an amount of from about 10%) to about 90% by weight; at least one binder present in an amount of from about 0% to about 5% by weight; a coat on the core in an amount of about 3% to about 4% by weight of the uncoated tablet core, wherein the composition is devoid of disintegrant. In another embodiment, the Brexpiprazole tablets of the present invention comprise a core comprising about 0.01% to about 40% by weight of Brexpiprazole or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof; at least one diluent present in an amount of from about \0% to about 90% by weight; at least one binder present in an amount of from about 0% to about 1% by weight; at least one disintegrant present in an amount of from about 1% to about 25% by weight of the uncoated core; a coat on the core in an amount of about 3% to about 4% by weight of the uncoated tablet core, wherein the diluent are selected from 20 L H I 1 8 - 1 1 - 2 0 1 7 11 : 4 5 the group of calcium phosphate, dibasic anhydrous, calcium phosphate, dibasic dihydrate, calcium phosphate tribasic, calcium sulphate, cellulose powdered, cellulose acetate, compressible sugar, confectioner's sugar, dextrates, dextrose, fructose, lactitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, polydextrose, sodium alginate, sorbitol, sucrose, trehalose and xylitol, or mixtures thereof. In another embodiment of the invention, the pharmaceutical compositions are formulated into solid oral pharmaceutical dosage forms. Solid oral pharmaceutical dosage forms include, but are not limited to, tablets, capsules, granules, pellets, beads, minitabs, spherules, beadlets, microcapsules, millispheres, microspheres, sachets, and the like. Preferably, the pharmaceutical composition refers to tablets. In another embodiment of the invention, the solid oral pharmaceutical composition comprising Brexpiprazole is prepared by wet or dry process. The wet and dry processes include, but are not limited to, wet granulation, dry granulation, and dry blending/ direct compression. Other formulation techniques are also contemplated within the scope of the present invention. Any pharmaceutical^ acceptable granulating agent can be used for wet granulation. Suitable granulating agents include water, esters such as ethyl acetate; ketones such as acetone; alcohols such as methanol, ethanol, isopropanol, butanol, and combinations thereof. In yet another embodiment of the invention, the solid oral pharmaceutical compositions comprise from about 0.05 mg to about 25 mg of Brexpiprazole. Preferably, the pharmaceutical compositions comprise 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg and 4 mg of Brexpiprazole. The final formulations may be coated or uncoated. For coating, additional excipients such as film-forming polymers, plasticizers, antiadherents, polishing agents, colorants, pigments, antifoaming agents, antisticking agents, and opacifiers are used. Film forming polymers include but are not limited to polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene glycol, hydroxypropyl methylcellulose and the like. In particular, film forming polymers include polyvinyl alcohol, polyvinyl pyrrolidone and polyethylene glycol. 21 L H I 1 0 - 1 1 - 2 0 ' 1 7 11 : 4 5" The tablet oral dosage form prepared by the above process can be subjected to in vitro dissolution evaluation according to Test 711 "Dissolution" in the United States Pharmacopoeia 37, United States Pharmacopoeia! Convention, Inc., Rockville, Md., 2014 ("USP") to determine the rate at which the active substance is released from the dosage form, and the content of the active substance can be determined in solution by high performance liquid chromatography. When comparing the test and reference products, dissolution profiles should be compared using a similarity factor (f2). The similarity factor is a logarithmic reciprocal square root transformation of the sum of squared error and is a measurement of the similarity in the percent (%) of dissolution between the two curves. f2= 50 • log {[1 + (l/n)It=in(Rt- Tt)2]"05* 100} Two dissolution profiles are considered similar when the h value is equal to or greater than 50. In another embodiment, the solid oral pharmaceutical composition of the present invention exhibits drug release in 900 ml of 0.05 M acetate buffer, pH 4.3, sampling at 10, 15, 20, 30 and 45 minutes using a USP II apparatus (paddle) at a temperature of 37±0.5°C and a rotation speed of 50 revolutions per minute (RPM) EXAMPLES The following examples are intended to further illustrate certain preferred embodiments of the invention and are not limiting in nature. Example 1 Table 1 Ingredients Brexpiprazole Mannitol Pregelatinized starch Colloidal silicon dioxide Magnesium stearate % w/w 4.45 84.05 10 0.50 1.00 Procedure: 22 1. Brexpiprazole, mannitol, pregelatinized starch, colloidal silicon dioxide were blended. 2. Magnesium stearate was mixed with the blend of step 1. 3. The mixture of step 2 was compressed into a tablet. 4. The tablet of step 3 can be optionally coated. Example 2 Table 2 Ingredients Brexpiprazole Mannitol Crospovidone Polyvinylpyrrolidone Colloidal silicon dioxide Magnesium stearate % w/w 4.45 86.05 5 3 0.50 1.00 Procedure: 1. Brexpiprazole, mannitol, crospovidone, polyvinylpyrrolidone, colloidal silicon dioxide were blended. 2. Magnesium stearate was mixed with the blend of step 1. 3. The mixture of step 2 was compressed into a tablet. 4. The tablet of step 3 can be optionally coated. Example 3 Table 3 Ingredients Brexpiprazole Microcrystalline cellulose Colloidal silicon dioxide Magnesium stearate % w/w 4.45 94.05 0.50 1.00 Procedure: 1. Brexpiprazole, microcrystalline cellulose, colloidal silicon dioxide were blended. 2. Magnesium stearate was mixed with the blend of step 1. 3. The mixture of step 2 was compressed into a tablet. 23 4. The tablet of step 3 can be optionally coated. Example 4 Table 4 Ingredients Brexpiprazole Lactose Microcrystalline cellulose Colloidal silicon dioxide Magnesium stearate % w/w 4.45 64.05 30.00 0.50 1.00 Procedure: 1. Brexpiprazole, lactose, microcrystalline cellulose, colloidal silicon dioxide are blended. 2. Magnesium stearate is mixed with the blend of step 1. 3. The mixture of step 2 is compressed into a tablet. 4. The tablet of step 3 can be optionally coated. Example 5 Table 5 Ingredients Brexpiprazole Mannitol Pregelatinized starch Colloidal silicon dioxide Magnesium stearate % w/w 4.45 84.05 10 0.50 1.00 Procedure: 1. Brexpiprazole, mannitol, pregelatinized starch, colloidal silicon dioxide were blended. 2. The blend of step 1 is compressed into slugs. 3. The slugs of step 2 are sifted to form granules. 4. The gratnules of step 3 are lubricated with magnesium stearate. 3. The lubricated granules of step 4 are compressed into a tablet. 4. The tablet of step 3 can be optionally coated. 24 ... Example 6 Table 6 Ingredients Brexpiprazole (in complex form with beta cyclodextrin) Lactose Crospovidone Polyvinylpyrrolidone Colloidal silicon dioxide Magnesium stearate % w/w 2.22 86.05 • 5 3 0.50 1.00 Procedure: 1. A complex of Brexpiprazole with beta-cyclodextrin is made. 2. Brexpiprazole of step 1, lactose, crospovidone, polyvinylpyrrolidone and colloidal silicon dioxide are blended. 2. Magnesium stearate is mixed with the blend of step 2. 3. The mixture of step 2 is compressed into a tablet. Table 7 shows the tablet properties of uncoated tablets obtained in Examples 1, 2 and 3. Disintegration test was performed using water as a test liquid. Table 7 Ingredients Hardness (Kp) Thickness (mm) Diameter (mm) Disintegration time (seconds) Example 1 6 3.14 6.00 40-70 Example 2 6 3.15 6.00 20-30 Example 3 6 3.17 6.00 50-60 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 and a pharmaceutically acceptable excipient, wherein the composition is substantially free of disintegrant and/or binder. 2. A solid oral pharmaceutical composition comprising Brexpiprazole and a pharmaceutically acceptable excipient, wherein the composition is substantially free of colorant. 3. A solid oral pharmaceutical composition comprising Brexpiprazole and a pharmaceutically acceptable excipient, wherein the composition has photostabilizers in an uncoated composition 4. A process for the preparation of a solid oral pharmaceutical composition comprising Brexpiprazole or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof, wherein the process comprises: (a) mixing Brexpiprazole optionally with at least one binder and/or disintegrant; (b) compacting the mixture of step a); (c) optionally milling the compacts of step b) using suitable screen; (d) lubricating the milled material of step c) with lubricant; (e) compressing the lubricated blend of step d) into tablets with a suitable tooling; and (f) optionally coating the tablets of step e). 5. A process for the preparation of a solid oral pharmaceutical composition comprising Brexpiprazole or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof, wherein the process comprises: (a) mixing Brexpiprazole optionally with at least one binder and/or disintegrant; (b) lubricating the mixture of step a) with a lubricant; (c) compressing the lubricated blend of step b) into tablets with a suitable tooling; and (d) optionally coating the tablets of step c). 6. A solid oral pharmaceutical composition comprising Brexpiprazole and a pharmaceutically acceptable excipient, wherein the composition comprises a core comprising Brexpiprazole and a coating layer over the core, and wherein the coating layer comprises a polymer selected from the group comprising polyvinyl alcohol, polyvinyl pyrrolidone or polyethylene glycol. 7. The composition of claim 1, wherein the disintegrant is crospovidone and/or binder is povidone. 8. The composition of claim 2, wherein the composition is substantially free of colorant in the coating layer. 9. The composition of claims 1 -5, wherein the composition is a tablet, pellet or a bead. 10. The composition of claims 1-6, wherein the pharmaceutical^ acceptable excipient is selected from the group comprising diluent, binder, disintegrant, lubricant, glidant, surfactant, or mixtures thereof.

Documents

Application Documents

# Name Date
1 201611038602-Form 1-101117.pdf 2017-11-28
1 201611038602-Other Patent Document-111116.pdf 2016-11-15
2 201611038602-Form 5-111116.pdf 2016-11-15
2 201611038602-Form 2(Title Page)-101117.pdf 2017-11-16
3 201611038602-Form 3-111116.pdf 2016-11-15
3 201611038602-Form 26-101117.pdf 2017-11-16
4 201611038602-Form 3-101117.pdf 2017-11-16
4 201611038602-Form 26-111116.pdf 2016-11-15
5 201611038602-Form 2(Title Page)-111116.pdf 2016-11-15
5 201611038602-Form 5-101117.pdf 2017-11-16
6 201611038602-Form 1-111116.pdf 2016-11-15
6 201611038602-Other Patent Document-101117.pdf 2017-11-16
7 201611038602-Form 1-111116.pdf 2016-11-15
7 201611038602-Other Patent Document-101117.pdf 2017-11-16
8 201611038602-Form 2(Title Page)-111116.pdf 2016-11-15
8 201611038602-Form 5-101117.pdf 2017-11-16
9 201611038602-Form 26-111116.pdf 2016-11-15
9 201611038602-Form 3-101117.pdf 2017-11-16
10 201611038602-Form 3-111116.pdf 2016-11-15
10 201611038602-Form 26-101117.pdf 2017-11-16
11 201611038602-Form 5-111116.pdf 2016-11-15
11 201611038602-Form 2(Title Page)-101117.pdf 2017-11-16
12 201611038602-Other Patent Document-111116.pdf 2016-11-15
12 201611038602-Form 1-101117.pdf 2017-11-28