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.
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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,
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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
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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.
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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
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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)
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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.
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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,
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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%.
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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
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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.
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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.
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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.