Claims:1. A pharmaceutical composition comprising brexpiprazole or a salt thereof a binder and a stabilizer.
2. The pharmaceutical composition according to claim 1, wherein the binder consisting of povidone or crospovidone and stabilizer selected from EDTA salts and ascorbic acid or its derivatives.
3. The pharmaceutical composition according to claim 1, further comprising a diluent/filler (a); a disintegrant (c) and a lubricant (d).
4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the diluent/filler (a) is at least one member selected from the group consisting of sugars, sugar alcohols, starches, and celluloses; the binder (b) consisting of povidone or crospovidone; the disintegrant (c) is at least one member selected from the group consisting of cellulose derivatives and starch derivatives; lubricant (d) is a stearate and stabilizer (e) selected from EDTA salts or ascorbic acid or its derivatives.
5. The pharmaceutical composition according to claim 4, wherein the diluent/filler (a) is at least one member selected from the group consisting of lactose, corn starch and microcrystalline cellulose; the binder (b) consisting of povidone or crospovidone; the disintegrant (c) is at least one member selected from the group consisting of low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium carboxymethyl starch and crospovidone; lubricant (d) is magnesium stearate and stabilizer (e) selected from EDTA salts or ascorbic acid or its derivatives.
6. The pharmaceutical composition according to claim 1 in the form of solid oral composition, preferably a tablet.
7. The pharmaceutical composition according to any one of claims 1 to 6, which is obtained by forming, into a tablet, a granulated substance obtained through wet granulation.
8. A method of producing solid oral pharmaceutical composition comprising brexpiprazole or a salt thereof as an active ingredient prepared by a process comprising steps of:
(1) granulating a mixture containing brexpiprazole or a salt thereof as an active ingredient or a salt thereof, a diluent/filler (a), a binder (b), and a disintegrant (c), farther mixing thereto a lubricant (d); and a stabilizer (e).
(2) forming the obtained mixture into a tablet,
wherein the diluent/filler (a) is at least one member selected from the group consisting of sugars, sugar alcohols, starches, and celluloses;
the binder (b) selected from povidone or crospovidone;
the disintegrant (c) is at least one member selected from the group consisting of cellulose derivatives and starch derivatives;
the lubricant (d) is a stearate; and the stabilizer (e) such as EDTA salts and ascorbic acid or its derivatives.
9. The method for producing the pharmaceutical composition according to claim 8, further comprising the step of: mixing a coating agent, a colorant, and a liquid medium to obtain a mixture, and coating the surface of the tablet using the mixture.
, Description:FIELD OF INVENTION
The present invention provides a stable solid oral pharmaceutical composition comprising brexpiprazole and a process for the preparation of said pharmaceutical composition. The present invention also relates to a pharmaceutical preparation which contains brexpiprazole having excellent storage stability and high photostability.
BACKGROUND
Brexpiprazole, i.e., 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one, has the following structural formula:

and known to have a dopamine D2 receptor partial agonist activity (D2 receptor partial agonist activity), a serotonin 5-HT2A receptor antagonist activity (5-HT2A receptor antagonist activity) and an adrenergic α1 receptor antagonist activity (α1 receptor antagonist activity) and, in addition thereto, concurrently has a serotonin uptake inhibitory action (or serotonin reuptake inhibitory action), and have a wide treatment spectrum for the central neurological diseases.

A drug instable against light is incorporated into a solid pharmaceutical preparation, through a known technique such as encapsulation or coating, so as to enhance photostability of the preparation.
Instead of coating, one known technique of enhancing photostability is through incorporation of a specific substance into a base material of a solid pharmaceutical preparation. Specifically, JP20007583 discloses an agent which has a lipid-soluble drug having poor stability against light, where the photostability of the lipid-soluble drug is improved by incorporation of a yellow or a red dye. JP2000191516 discloses an agent having improved photostability, in which a drug having poor stability against light is improved in its photostability by incorporation of a colorant. This patent document also discloses that, when the agent further contains titanium oxide, the effect of enhancing photostability can be further potentiated.
PCT patent publication WO2013054872 (US20160158227) discloses a pharmaceutical composition comprising brexpiprazole, wherein, when povidone or crospovidone was used as a binder, the obtained tablet tends to have reduced photostability and storage stability. This patent application also discloses that the coated tablet (film-coated tablet) provided with a coating layer is preferable to achieve long-term storage stability and prevent degradation due to light.
In order to solve the above problems, the present inventors have carried out extensive studies on the approach for preventing the incompatibility of drug with povidone or crospovidone and also preventing degradation of the product.

Through further studies, the inventors have found that incorporation of stabilizers such as EDTA salts and ascorbic acid or its derivatives along with povidone or crospovidone as a binder in the pharmaceutical preparation comprising brexpiprazole successfully prevents degradation of product due to light and achieve long-term storage stability. The present invention has been accomplished on the basis of these findings.

SUMMARY OF THE INVENTION

Accordingly, in a first object of the present invention provides a pharmaceutical composition comprising brexpiprazole having excellent storage stability and high photostability.
Another major object of present invention provides pharmaceutical composition comprising brexpiprazole or a salt thereof as an active ingredient, a binder and a stabilizer.
In one embodiment present invention provides pharmaceutical composition comprising brexpiprazole or a salt thereof as an active ingredient, wherein the binder consisting of cellulose derivatives, povidones or crospovidone and stabilizer selected from EDTA salts and ascorbic acid or its derivatives.
Another object of present invention provides pharmaceutical composition comprising brexpiprazole or a salt thereof as an active ingredient with a binder and a stabilizer, further comprising a diluent/filler (a); a disintegrant (c) and a lubricant (d).
In one embodiment present invention provides pharmaceutical composition comprising brexpiprazole or a salt thereof as an active ingredient and further comprising a diluent/filler (a), a binder (b), a disintegrant (c) a lubricant (d) and a stabilizer (e) wherein the diluent/filler (a) is at least one member selected from the group consisting of sugars, sugar alcohols, starches, and celluloses; the binder (b) consisting of cellulose derivatives, or povidones; the disintegrant (c) is at least one member selected from the group consisting of cellulose derivatives and starch derivatives; lubricant (d) is a stearate and stabilizer (e) such as EDTA salts and ascorbic acid or its derivatives.
Another embodiment of present invention provides pharmaceutical composition comprising brexpiprazole or a salt thereof as an active ingredient and further comprising lactose, corn starch, microcrystalline cellulose or like diluent/filler; low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, crospovidone, or like disintegrant; and povidone, hydroxypropyl cellulose or like binder; lubricant is magnesium stearate and stabilizers such as EDTA salts and ascorbic acid or its derivatives.
Another object of present invention provides pharmaceutical composition comprising brexpiprazole or a salt thereof as an active ingredient in the form of solid oral composition, preferably a tablet.

One object of the present invention is to provide a solid oral pharmaceutical composition or a tablet comprising brexpiprazole or a salt thereof as an active ingredient prepared by a process comprising steps of:

(1) granulating a mixture containing brexpiprazole or a salt thereof as an active ingredient or a salt thereof, a diluent/filler (a), a binder (b), and a disintegrant (c), farther mixing thereto a lubricant (d); and a stabilizer (e).

(2) forming the obtained mixture into a tablet,

wherein the diluent/filler (a) is at least one member selected from the group consisting of sugars, sugar alcohols, starches, and celluloses;

the binder (b) selected from cellulose derivative or povidone;
the disintegrant (c) is at least one member selected from the group consisting of cellulose derivatives and starch derivatives;

the lubricant (d) is a stearate; and

the stabilizer (e) such as EDTA salts and ascorbic acid or its derivatives
the method for producing the tablet, further comprising the step of:
(3) mixing a coating agent, a colorant (f), and a liquid medium to obtain a mixture, and coating the surface of the tablet using the mixture.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a pharmaceutical composition comprising brexpiprazole or a salt thereof as an active ingredient and a process for the preparation of said pharmaceutical composition.

The term 'pharmaceutical composition' as used herein includes solid dosage forms such as tablet, capsule, pill and the like. These dosage forms may be prepared by processes known in the art including, for example, comminuting, mixing, granulating, melting, sizing, filling, drying, molding, immersing, coating, compressing, etc.

In one embodiment, the present invention provides a pharmaceutical composition comprising brexpiprazole or a salt thereof as an active ingredient and pharmaceutically acceptable excipients.

Another major object of present invention provides a pharmaceutical composition comprising brexpiprazole or a salt thereof as an active ingredient, a binder and a stabilizer.
In one embodiment present invention provides a pharmaceutical composition comprising brexpiprazole or a salt thereof as an active ingredient, wherein the binder consisting of cellulose derivatives, povidones or crospovidone and stabilizer selected from EDTA salts and ascorbic acid or its derivatives.
Another object of present invention provides a pharmaceutical composition comprising brexpiprazole or a salt thereof as an active ingredient with a binder and a stabilizer, further comprising a diluent/filler (a); a disintegrant (c) and a lubricant (d).
Another object of present invention provides a pharmaceutical composition comprising brexpiprazole or a salt thereof as an active ingredient in the form of solid oral composition, preferably a tablet.

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.

The tablet of the present invention preferably comprises additives such as a diluent/filler (a), a binder (b), a disintegrant (c), a lubricant (d) and a stabilizer (e).
The use of the terms “a” and "an” and "the” and similar referents 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.

Throughout this specification and the appended claims, it is to be understood that the words "comprise", “have”, “contain” and "include" and variations such as "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.

The term “brexpiprazole” used herein comprises 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one in accordance with formula (1) above. Further, the term "brexpiprazole" comprises all the pharmaceutically acceptable salts, polymorphs, hydrates and/or solvates thereof.

Pharmaceutical excipients according to present invention may comprise diluent, filler binder, diluent, disintegrant, lubricant, surfactant and the like. Example and suitable amount of said optional excipient is known to a skilled person or as given in Handbook of pharmaceutical excipients (sixth edition, 2009).

A diluent/filler according to present invention includes for example, sugar such as fructose, white soft sugar, sucrose, lactose, powdered hydrogenated maltose starch syrup, and maltose; sugar alcohols such as D-mannitol, D-sorbitol, xylitol, erythritol, maltitol; starch such as wheat starch, corn starch, and potato starch; starch derivatives such as dextrin, beta-cyclodextrin; cellulose or a derivative thereof such as microcrystalline cellulose, powdered cellulose, ethyl cellulose, carboxymethyl cellulose (carmellose), sodium carboxymethyl cellulose (carmellose sodium), and microcrystalline cellulose/carmellose sodium; anhydrous silicic acid, hydrated silicon dioxide, silicon dioxide, calcium silicate, magnesium silicate, and magnesium aluminometasilicate; kaolin; titanium oxide; magnesium oxide; talc; precipitated calcium carbonate or anhydrous dibasic calcium phosphate.

A binder according to present invention includes sucrose; white soft sugar; pregelatinized starch; partially pregelatinized starch; cellulose or a derivative thereof such as microcrystalline cellulose, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose (carmellose sodium), hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose (hypromelloses such as hypromellose 2208, hypromellose 2906, and hypromellose 2910); other polysaccharides such as acacia, powdered acacia, agar, powdered agar, guar gimp tragacanth, powdered tragacanth, pullulan, and pectin; acrylic acid based polymer such as methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, ethyl acrylate-methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer E, and aminoalkyl methacrylate copolymer RS; sodium alginate; purified gelatin;
hydrolyzed gelatin powder; carboxyvinyl polymer; copolyvidone; povidone or polyvinyl alcohol.

A disintegrant according to present invention includes starch or a derivative thereof such as wheat starch, corn starch, potato starch, partially pregelatinized starch, sodium carboxymethyl starch, and hydroxypropyl starch; cellulose or a derivative thereof such as microcrystalline cellulose, carboxymethyl cellulose (carmellose), calcium carboxymethyl cellulose (carmellose calcium), croscarmellose sodium, and low-substituted hydroxypropyl cellulose; crospovidone; alginic acid; or bentonite.

A lubricant according to present invention includes stearic acid or a salt thereof such as stearic acid, aluminum stearate, calcium stearate, and magnesium stearate; carnauba wax; glycerol ester of fatty acid; hydrogenated oil; yellow beeswax; white beeswax; talc; sodium stearyl fumarate; and polyethylene glycol (macrogols such as macrogol 400, macrogol 600, macrogol 1500, macrogol 4000, and macrogol 6000).

Another object of present invention provides a solid oral pharmaceutical composition comprising brexpiprazole or a salt thereof as an active ingredient and further comprising a diluent/filler (a), a binder (b), a disintegrant (c) a lubricant (d) and a stabilizer (e) wherein the diluent/filler (a) is at least one member selected from the group consisting of sugars, sugar alcohols, starches, and celluloses; the binder (b) consisting of cellulose derivatives and povidones; the disintegrant (c) is at least one member selected from the group consisting of cellulose derivatives and starch derivatives; lubricant (d) is a stearate and stabilizer (e) such as EDTA salts and ascorbic acid.
Another embodiment of present invention provides a solid oral pharmaceutical composition comprising brexpiprazole or a salt thereof as an active ingredient and further comprising lactose, corn starch, microcrystalline cellulose or like diluent/filler; low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, crospovidone or like disintegrant; and povidone, hydroxypropyl cellulose or like binder; lubricant is magnesium stearate and stabilizers such as EDTA salts and ascorbic acid.
A pharmaceutical composition according to present invention comprising brexpiprazole or a salt thereof as an active ingredient is a solid composition 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.

The tablet of the present invention may comprise other components in addition to the diluent/filler (a), the binder (b), the disintegrant (c), the lubricant (d) and the stabilizer (e). Examples of other components include various additives applicable to tablets, such as colorants, pH adjusters, preservatives, absorbefacients, taste enhancers, antioxidants, buffers, chelating agents, abrasives, solvents, hardening agents, surfactants, sweeteners, fluidizers, brightening agents, and flavors. Those components may be used in an amount that does not adversely affect the present invention.

The tablet, of the present invention may be used as an uncoated tablet that comprises the above described components but does not have a coating layer provided thereon.

A coated tablet (film-coated tablet) provided with a coating layer is preferable to achieve long-term storage stability and prevent degradation due to light or the like.
The coating layer may comprise pharmaceutical additives, such as a coating agent, plasticizer, dispersant, defoaming agent, and the like, usually used for coating (for providing a coat to) orally administrable pharmaceutical preparations.

A coating can be applied using the materials and methods known to a person skilled in the art. Examples of film coating material includes Opadry® which is Colorcon's customized, one-step film coating system which combines polymer, plasticizer, opacifier, and pigment, as required, in a dry concentrate.

Another embodiment of the invention provides a solid oral pharmaceutical composition comprising brexpiprazole prepared by a process comprising steps of:

(1) granulating a mixture containing brexpiprazole or a salt thereof as an active ingredient or a salt thereof, a diluent/filler (a), a binder (b), and a disintegrant (c), farther mixing thereto a lubricant (d); and a stabilizer (e).

(2) forming the obtained mixture into a tablet,

wherein the diluent/filler (a) is at least one member selected from the group consisting of sugars, sugar alcohols, starches, and celluloses;

the binder (b) selected from cellulose derivative or povidones;
the disintegrant (c) is at least one member selected from the group consisting of cellulose derivatives and starch derivatives;

the lubricant (d) is a stearate; and

the stabilizer such as EDTA salts and ascorbic acid
the method for producing the tablet, further comprising the step of:
(3) mixing a coating agent, a colorant (e), and a liquid medium to obtain a mixture, and coating the surface of the tablet using the mixture.

The order of steps in the process of preparation of solid oral pharmaceutical compositions according to present invention is for the purpose of representation only and should not limit the scope of the embodiments with respect to performance of steps in the mentioned sequence.

The method for producing the tablet of the present invention is not particularly limited; for example, the tablet of the present invention can be produced by a step of forming into a tablet a mixture containing brexpiprazole or a salt thereof, and components other than brexpiprazole or a salt thereof necessary to form a tablet (i.e., a diluent/filler (a), a binder (b), a disintegrant (c), a lubricant (d), a stabilizer (e) and the like). Alternatively, the tablet of the present invention can be produced by the method comprising: granulating a mixture containing brexpiprazole or a salt thereof, a diluent/filler (a), a binder (b), disintegrant (c), and a stabilizer (e) and further mixing thereto a lubricant (d); and forming the obtained mixture into a tablet.
The granulation method used for forming the granulated substance into a tablet is not particularly limited. Examples thereof include dry granulation methods and wet granulation methods (e.g., a fluidized-bed granulation method, and a knead-granulation method). Among these, wet granulation methods are preferably used for the production, from a standpoint of being able to uniformly mix the active ingredient and other components in the tablet, and being able to obtain a tablet whose components are uniformly distributed therein.

Examples of the tablet forming methods include tableting, such as direct compression tableting, dry tableting, wet tableting, and external lubrication tableting.
The coated tablet of the present invention can be produced by mixing a coating agent, a colorant (e), and a liquid medium; spraying the obtained liquid mixture on the surface of the uncoated tablet obtained by the method described above; and successively drying it.

The solid oral pharmaceutical composition/tablet of the present invention comprising brexpiprazole as disclosed in the Table 1 has exhibited to have excellent disintegration ability, storage stability, and photostability. Therefore, the solid oral pharmaceutical composition/tablet of the present invention is highly usable in the medical field.

The invention will be further illustrated by the following examples, however, without restricting its scope to these embodiments.
Examples
Table 1

Brexpiprazole Composition/Tablet (4 mg) - Batch No. 4/005
Sr. No. Ingredients %w/w
Granulation
1 Brexpiprazole 4.30
2 Lactose monohydrate 51.05
3 Corn starch 21.51
4 Microcrystalline cellulose (Avicel PH 101) 10.75
5 Sodium starch glycolate (Type A) 6.21
6 Povidone K30 1.51
7 Sodium sulfite 0.25
8 Disodium EDTA 0.56
9 Purified water Q.S.
Lubrication
10 Magnesium Stearate 0.65
Core Tablet weight 96.77
Film coating
11 Opadry white 3.23
12 Purified water Q.S.
Total weight 100.00

Stability studies:
The stability data obtained, especially reduction of impurities with the stabilizers EDTA salt and ascorbic acid with brexpiprazole alone and EDTA salt with brexpiprazole composition/tablet are listed in Table 2, Table 3, Table 4 and Table 5, respectively.
Table 2

Brexpiprazole Brexpiprazole + PVP K30 Brexpiprazole + Ascorbic acid Brexpiprazole + PVP K30 + Crosspovidone XL 10 + Ascorbic acid
Initial 1M_40 oC/75% Open Initial 1M_40 oC/75% Open Initial 1M_40 oC/75% Open Initial 3Days-50oC/90%RH
Open 3Days-50oC/90%RH
Close
Known impurities (% impurity)
N-Oxide 0.01 0.01 0.02 2.78 0.01 0.03 0.02 0.12 0.04
Unknown imp
Single max 0.08 0.07 0.07 0.07 0.06 0.06 0.05 0.05 0.05
Total-known 0.01 0.03 0.02 2.80 0.01 0.04 0.02 0.12 0.04
Total-Known + Unknown 0.19 0.19 0.35 3.02 0.30 0.23 0.20 0.28 0.21

Table 3

Brexpiprazole Brexpiprazole + PVP K30 Brexpiprazole + Disodium EDTA Brexpiprazole + PVP K30 + EDTA
Initial 1M_
40 oC /75% Open Initial 1M_40 oC/75%
Open Initial 1M_40 oC/75% Open Initial Heat_80oC48h Open Moist Pho contr_1.2k Lux_22h Pho uncontr_1.2k Lux_22h
Known impurities
(% impurity)
N- Oxide 0.01 0.01 0.02 2.78 0.01 0.01 0.11 0.06 0.11 0.12 0.13
Unknown imp
Single max 0.08 0.07 0.06 0.07 0.07 0.07 0.07 0.04 0.08 0.07 0.06
Total-known 0.01 0.03 0.02 2.80 0.01 0.01 0.11 0.06 0.11 0.12 0.13
Total Known + Unknown 0.19 0.19 0.34 3.02 0.34 0.17 0.33 0.16 0.34 0.31 0.36

Table 4

Stability Data of Brexpiprazole Composition at 40 oC/75% H Impurities
Condition N- Oxide SMUI Total
Initial BQL BQL 0.09
Without Canister @ 1 Month BQL BQL 0.09
Without Canister @ 3 Months

Stress study Data of Brexpiprazole Composition (for 7 Days) N- Oxide
Initial 50/90 Open 50/90 close
Brexpiprazole Composition 0.01 BQL BQL

Table 5

Photo Stability Data of Brexpiprazole Composition/Tablet Impurities
Condition N- Oxide SMUI Total
Controlled BQL 0.07 0.15
Un-controlled (Exposed) BQL 0.07 0.19