FIELD OF THE INVENTION
The present invention relates to pharmaceutical compositions of Lurasidone or its
pharmaceutical^ acceptable salts, esters, solvates, polymorphs, stereoisomers or
mixtures thereof. The present invention also relates to a process for the preparation of
solid oral dosage forms comprising Lurasidone or its pharmaceutically acceptable
salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof, wherein the
dosage form exhibits satisfactory pharmaceutical technical attributes.
BACKGROUND OF THE INVENTION
Lurasidone is a well-known dopaminergic (D2) and serotonin (5-HT2A) receptor
antagonist and is disclosed in U.S. Patent Nos. 5,780,632 and U.S. 5,532,372.
Chemically, it is known as (3aR,4S,7R,7aS)-2-{(lR,2R)-2-[4-(l,2-benzisothiazol-3-
yl)piperazin-l-ylmethyl] cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-
1,3-dione hydrochloride having the structural formula:
H H
' ^ y W * HCI
Lurasidone is known to have psychotropic activities and is therapeutically used for
the treatment of schizophrenia and senile dementia.
Lurasidone hydrochloride is marketed in the United States under the brand name
Latuda® for the treatment of schizophrenia and Depressive episodes associated with
bipolar I disorder by Sunovion Pharms. Inactive ingredients in Latuda® consist of
mannitol, pregelatinized starch, croscarmellose sodium, hypromellose, magnesium
stearate, Opadry® and carnauba wax.
5 - 8 7 - 2 0 1 7 1
U.S. Patent No. 7,727,553 assigned to Dainippon Sumitomo Pharma discloses a
pharmaceutical preparation in the form of a rapidly disintegrating oral preparation
comprising Lurasidone granules, a first disintegrating agent, a water-soluble
excipient, a water soluble polymer binder and a second disintegrating agent.
U.S. Patent No. 8,729,085 assigned to Dainippon Sumitomo Pharma Co., Ltd.
discloses composition comprises Lurasidone, a pregelatinized starch, a water-soluble
excipient and water-soluble polymer binder. The said publication highlights the use
of pregelatinized starch in the range of 10% to 50% to facilitate dissolution of said
composition.
U.S. Patent No. 8,883,794 and 9,555,027 assigned to Dainippon Sumitomo Pharma
Co., Ltd. relate to oral preparation comprising Lurasidone in range of 20 to 45% w/w,
pregelatinized starch in range of 10 to 50% w/w, a water-soluble excipient, and a
water-soluble polymeric binder in the range of 0.5 to 10% w/w wherein the
preparation exhibits an invariant level of elution behaviour even when the content of
its active ingredient is varied.
U.S. Patent Publication No. 9,433,620 assigned to Cadila Healthcare discloses
pharmaceutical compositions of Lurasidone with one or more water-insoluble
pharmaceutical excipients and water-insoluble binders, wherein the composition is
free of pregelatinized starch.
U.S. Patent Publication No. 2014/0343076 assigned to Cadila Healthcare discloses
pharmaceutical compositions of Lurasidone with one or more acids, wherein
formulations have a similar in vitro dissolution profile to Latuda®.
3
0 ; S - G 7 - - 2 G 1 7 17 :QB
PCT publication No. WO2014/076712 assigned to Hetero Research discloses
amorphous solid dispersion of Lurasidone hydrochloride in combination with a
pharmaceutically acceptable carrier.
U.S. Patent Publication No. 2015/0157628 assigned to Aurobindo discloses oral
pharmaceutical composition comprising an atypical antipsychotic as an active agent,
starch or a starch derivative, optionally with at least one or more other
pharmaceutically acceptable excipient.
PCT publication No. WO2016/012898 assigned to Lupin discloses oral
pharmaceutical composition of Lurasidone, water-soluble pharmaceutical excipients
and single disintegrating agent, wherein the said composition is devoid of starch.
Development of an immediate release solid oral dosage forms of Lurasidone
Hydrochloride with desired and optimum technical attributes like optimum
dissolution profile and good disintegration is very challenging. The poor aqueous
solubility of drug and other challenges as briefly discussed in above mentioned prior
arts pose significant problem in the design of pharmaceutical formulations
comprising Lurasidone Hydrochloride.
The above cited prior arts disclose various approaches to prepare pharmaceutical
compositions of Lurasidone Hydrochloride by using water-soluble excipients (i.e.
water-soluble polymer binders, disintegrating agents), water-insoluble excipients (i.e.
water-insoluble binders, water-insoluble disintegrating agents), acids (i.e. organic
acids and/or an inorganic acids), free of starch, and amorphous solid dispersion, to
name a few. However, there is no disclosure or teaching/suggestion in the prior art
about development of improved and alternate formulations of Lurasidone or salts
thereof, wherein the extra-granular phase of the formulation is free of a binder, a
disintegrant, and a diluent and further comprises fewer amount of starch (less than
4
I O S - 0 7 - 2 8 1 7 17 : 88
10% w/w), which can also exhibit rapid disintegration as well as equivalent in vitro
dissolution profile.
The pharmaceutical compositions of Lurasidone Hydrochloride suitable for oral
administration to humans must have desirable chemical and physical properties,
dissolution, stability and bioequivalence complying with demanding requirements
and regulations of health and medicine regulatory agencies across the world,
especially USFDA, MHRA, Health Canada, PMDA and TGA.
The present inventors developed a cost-effective solid oral pharmaceutical
composition of Lurasidone Hydrochloride without compromising on desirable
formulation technical attributes of the prepared dosage form in comparison to
reference dosage form (Latuda®). The present invention further provides a simple,
economical and industrially feasible process for preparing pharmaceutical
composition of Lurasidone Hydrochloride.
OBJECTIVE AND SUMMARY OF THE INVENTION
It is a principal object of the present invention to provide a pharmaceutical
composition comprising Lurasidone or its pharmaceutically acceptable salts, esters,
solvates, polymorphs, enantiomers or mixtures thereof with one or more
pharmaceutically acceptable excipient.
It is another object of the present invention to provide a process for the preparation of
pharmaceutical composition comprising Lurasidone or its pharmaceutically
acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof.
It is another object of the present invention to provide a pharmaceutical composition
comprising Lurasidone or its pharmaceutically acceptable salts, esters, solvates,
5
I 0 5 - 0 7 - 2 0 1 7 1 7 : 00
polymorphs, enantiomers or mixtures thereof and one or more pharmaceutically
acceptable excipient(s); and less than 10% w/w of starch, wherein the extragranular
phase of the composition is free of at least one excipient selected from a binder,
disintegrant and/or diluent.
It is another object of the present invention to provide a solid oral pharmaceutical
composition comprising Lurasidone or its pharmaceutically acceptable salts, esters,
solvates, polymorphs, enantiomers or mixtures thereof further comprising at least one
or more pharmaceutically acceptable excipients like diluent, binder, disintegrant,
glidant, surfactant, wetting agent, lubricant, solubilizer, stabilizer, sweetener,
flavoring agent and coloring agent.
Another object of the present invention is to develop pharmaceutical compositions of
Lurasidone Hydrochloride that make the granulation process more consistent and
therefore feasible for industrial production, while maintaining stability and
pharmaceutical equivalence to the reference listed drug.
The following embodiments further describe the objects of the present invention in
accordance with the best mode of practice, however, disclosed invention is not
restricted to the particular embodiments hereinafter described.
In accordance with a preferred embodiment of the present invention, there is provided
a pharmaceutical composition comprising Lurasidone or its pharmaceutically
acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof with
comparable dissolution profile in comparison to reference dosage form (Latuda®).
In accordance with another embodiment of the present invention, there is provided a
pharmaceutical composition comprising granules of Lurasidone or its
pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or
6
mixtures thereof, one or more pharmaceutical!)/ acceptable excipient(s); and less than
10% w/w of starch.
In accordance with yet another embodiment of the present invention, there is
provided a pharmaceutical composition comprising granules of Lurasidone or its
pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or
mixtures thereof, at least one or more pharmaceutically acceptable excipient, and less
than 10% w/w of starch, wherein the extragranular phase of the composition is free of
a binder.
In accordance with one other embodiment of the present invention, there is provided
a pharmaceutical composition comprising granules of Lurasidone or its
pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or
mixtures thereof, one or more pharmaceutical excipient(s), and less than 10% w/w of
starch, wherein the extragranular phase of the composition is free of a disintegrant.
In accordance with yet another embodiment of the present invention, there is
provided a pharmaceutical composition comprising granules of Lurasidone or its
pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or
mixtures thereof, one or more pharmaceutical excipient(s), and less than 10% w/w of
starch, wherein the extragranular phase of the composition is free of a diluent.
In accordance with yet another embodiment of the present invention, there is
provided a pharmaceutical composition comprising granules of Lurasidone or its
pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or
mixtures thereof, one or more pharmaceutical excipient(s), and less than 10% w/w of
starch, wherein the extragranular phase of the composition is free of a binder, a
disintegrant and a diluent.
7
I 85>Q7 -2 ©17 17 :Q.Q.
In accordance with still another embodiment of the present invention, there is
provided a pharmaceutical composition comprising granules of Lurasidone or its
pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or
mixtures thereof, one or more pharmaceutical excipient(s); wherein granules of
Lurasidone are prepared by utilizing a suitable amount of surfactant to facilitate
solubilization of active ingredient.
In accordance with still another embodiment of the present invention, there is
provided a pharmaceutical composition comprising granules of Lurasidone or its
pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or
mixtures thereof, one or more pharmaceutical excipient(s) including one or more
binder, disintegrant, surfactant and/or diluent, and less than 10% w/w of starch,
wherein the said excipient(s) are present only in the intragranular phase of the
composition.
In accordance with still another embodiment of the present invention, there is
provided a solid oral dosage form of Lurasidone or salts thereof, wherein the dosage
form comprises an intragranular phase and an extragranular phase. The intragranular
phase comprises granules of Lurasidone or salts thereof, and one or more of a binder,
a disintegrant, a diluent, a surfactant and less than 10% w/w of starch.
In accordance with still another embodiment of the present invention, there is
provided a pharmaceutical composition comprising granules of Lurasidone or its
pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or
mixtures thereof, one or more pharmaceutical excipient(s) including a binder, a
disintegrant and/or a diluent, and less than 10% w/w of starch, wherein the
intragranular disintegrant may be present alone or combination with two or more
disintegrants.
8
I 05-87 - 2817 17 :88
In accordance with still another embodiment of the present invention, there is
provided a pharmaceutical composition of Lurasidone or its pharmaceutically
acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof
comprising at least one binder, disintegrant, diluent, filler, lubricant, glidant,
surfactant, sweetener, flavor and less than 10% w/w of starch.
In accordance with still another embodiment of the present invention, there is
provided a process for the preparation of a pharmaceutical composition comprising
Lurasidone or its pharmaceutically acceptable salts, esters, solvates, polymorphs,
enantiomers or mixtures thereof, comprising the steps of a) Sifting the accurately
weighed quantities of active agent and one or more pharmaceutically acceptable
excipient(s) through a suitable sieve followed by mixing; b) Granulating the mixture
of step a) with an binder solution (granulation in an aqueous or non-aqueous solvent);
c) Drying the granulated mass, optionally milling of the dried granules and mixed the
sifted granules; d) lubricated the sifted blend of step c); e) Compressing the lubricated
granules into tablets or filling in capsules.
In accordance with still another embodiment of the present invention, there is
provided a pharmaceutical composition comprising Lurasidone or its
pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or
mixtures thereof, comprising the steps of: (a) blending a mixture of Lurasidone
hydrochloride and at least one pharmaceutically acceptable excipient including a
binder and/or a disintegrant; (b) optionally compacting the blended material using
roller compactor; (c) optionally milling the compacted material; (d) blend from step
(a) or milled material from step (c) was lubricated with a suitable lubricant; (e)
lubricated blend or granules from (d) was compressed into tablets with a suitable
tooling or filled in capsules.
9
I G S - Q 7 - 20-17 17 : GO
In accordance with still another embodiment of the present invention, there is
provided an immediate-release pharmaceutical composition comprising Lurasidone or
salts thereof wherein the composition is free of any acidic components, in particular
the composition is free of any organic and/or inorganic acids.
In accordance with still another embodiment of the present invention, there is
provided an immediate-release pharmaceutical composition comprising Lurasidone or
salts thereof, wherein 10-40% of the granules are retained on the ASTM (American
Society for Testing and Materials) standards #60 mesh sieve. Preferably, 5-20% of
the granules are retained on the ASTM (American Society for Testing and Materials)
standards #40 mesh sieve.
In accordance with still another embodiment of the present invention, there is
provided a solid oral dosage form comprising a pharmacologically effective amount
of Lurasidone or its pharmaceutical^ acceptable salts, esters, solvates, polymorphs,
stereoisomers or mixtures thereof present in an amount of about 30% to about 95%
by weight wherein, the composition exhibits technical attributes such as tablet size,
dissolution, stability and bioequivalence that is comparable to the commercially
available counterpart (LATUDA® Tablets) and a process for preparing the same.
In accordance with still another embodiment of the present invention, there is
provided use of a pharmaceutical composition in the manufacture of a medicament
for treating schizophrenia, major depressive episodes associated with bipolar I
disorder, memory or learning dysfunctions caused by schizophrenia, senile dementia,
attention deficit hyperactivity disorder, central nervous system disorder responsive to
modulation of glutamate levels and other associated CNS disorders.
10
LH-I Q S - Q ? - 2 B I 7 1 7 : QO
DETAILED 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 an antipsychotic drug, preferably
Lurasidone or its pharmaceutical^ acceptable salts, esters, solvates, polymorphs,
enantiomers or mixtures thereof, and 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, granules, tablets (single layered tablets, multi-layered
tablets, bioadhesive tablets, caplets, matrix tablets, tablet within a tablet,
mucoadhesive tablets, modified release tablets, pulsatile release tablets, timed release
tablets, delayed release, controlled release, extended release and sustained release
tablets), capsules (immediate or modified release) (hard and soft or liquid filled soft
gelatin capsules), pills, troches, sachets, powders, microcapsules, mini-tablets, tablets
in capsules and microspheres, matrix composition and the like. Preferably, the
pharmaceutical composition refers to tablets and capsules. More preferably, the
pharmaceutical composition refers to immediate release oral tablets, which may be
uncoated or film coated.
As used herein, the term " Lurasidone1" is used in broad sense to include not only "
Lurasidone'" per se but also its pharmaceutical^ acceptable salts, pharmaceutical^
acceptable solvates, pharmaceutical^ acceptable hydrates, pharmaceutical^
acceptable enantiomers, pharmaceutical ly acceptable derivatives, pharmaceutical ly
acceptable isomers, pharmaceutical^ acceptable polymorphs, pharmaceutical^
acceptable prodrugs thereof, and also its various crystalline and amorphous forms.
11
HI 0 5 - G 7 - 2 0 1 7 17 : 0 0
The term 'Lurasidone' hydrochloride' used in this specification means the S-isomer
in substantially pure form, i.e. at least about 98% pure.
The term "excipient" means a pharmacologically inactive component such as a
diluent, binder, disintegrant, glidant, surfactant, wetting agent, lubricant, solubilizer,
stabilizer sweetener, flavoring agent, coloring agent and 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. The excipient(s)
may be present intra-granularly or extra-granularly or in both the phases in any form.
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.
"Substantially free" as used herein refers to the pharmaceutical composition of
Lurasidone or salts thereof, which is free from conversion to other polymorphic
forms during formulation development or stability studies and/or which comprises
less than 0.1% w/w of superdisintegrant by total weight of the composition.
Unless otherwise stated the weight percentages expressed herein are based on the
final weight of the composition or formulation.
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.
12
I 0 - 5 - 8 7 - 2 - 8 1 7 17 : 00
As used herein, the term "about" means ± approximately 20% of the indicated value,
such that "about 10 percent" indicates approximately 08 to 12 percent.
As used herein, the term "intra-granular" (part/phase/portion) refers to the
components of formulation of the present invention that are within granules. As used
herein, the term "extra-granular" (part/phase/portion) refers to those components of
formulation of the present invention that are outside the granules.
The pharmaceutical compositions of present invention comprise about 1 to about 160
mg of Lurasidone or salts thereof, preferably about 20 to about 120 mg of Lurasidone
Hydrochloride. The pharmaceutical . composition comprises Lurasidone
Hydrochloride in the range of about 10% to about 95% by weight, preferably in the
range of about 20% to about 45% by weight on the basis of the total weight of the
composition.
Further, inventors of the present invention have found that Lurasidone formulations
of the invention even while containing wide range of dose, exhibit similar in-vitro
(dissolution) profile.
The compositions of the present invention comprise Lurasidone or its
pharmaceutical^ acceptable salts, esters, solvates, polymorphs, stereoisomers or
mixtures thereof having D90 less than or equal to about 80 pm and D50 less than or
equal to about 40 pm. Preferably, the D90 ranges between 5 pm and 50 pm and D50 is
less than 30 jam. The particle size of Lurasidone Hydrochloride can be measured by
suitable techniques such as Laser light scattering (e.g. Malvern Light Scattering),
Coulter counter, microscopy and any other technique known in the art.
The present invention relates to a pharmaceutical composition of Lurasidone or salts
LHI 0 5 - 0 7 - 2 8 1 7 17 :QG
thereof, comprising granules of Lurasidone or its pharmaceutically acceptable salts,
esters, solvates, polymorphs, stereoisomers or mixtures thereof and one or more
pharmaceutical excipient(s); and less than 10% w/w of starch. It further relates to the
process for preparing such composition.
In another embodiment, the present invention includes a pharmaceutical composition
of Lurasidone or its pharmaceutically acceptable salts, esters, solvates, polymorphs,
stereoisomers or mixtures thereof comprising granules of Lurasidone or salts thereof,
one or more pharmaceutical excipient(s), and less than 10% w/w of starch, wherein
the extragranular phase of the composition is free of a binder.
In another embodiment, the present invention includes a pharmaceutical composition
of Lurasidone or its pharmaceutically acceptable salts, esters, solvates, polymorphs,
stereoisomers or mixtures thereof comprising granules of Lurasidone or salts thereof,
one or more pharmaceutical excipient(s), and less than 10% w/w of starch, wherein
the extragranular phase of the composition is free of a disintegrant.
In another embodiment, the present invention includes a pharmaceutical composition
of Lurasidone or its pharmaceutically acceptable salts, esters, solvates, polymorphs,
stereoisomers or mixtures thereof comprising granules of Lurasidone or salts thereof,
one or more pharmaceutical excipient(s), and less than 10% w/w of starch, wherein
the extragranular phase of the composition is free of a diluent.
In another embodiment, the present invention includes a pharmaceutical composition
of Lurasidone or its pharmaceutically acceptable salts, esters, solvates, polymorphs,
stereoisomers or mixtures thereof comprising granules of Lurasidone or salts thereof,
one or more pharmaceutical excipient(s), and less than 10% w/w of starch, wherein
the extragranular phase of the composition is free of a binder, a disintegrant, and/or a
diluent.
14
LHI 05-8-7 - 2 8 1 7 17 : 88
In another embodiment, the present invention includes a solid oral dosage form of
Lurasidone or salts thereof, wherein the dosage form comprises an intragranular
phase and an extragranular phase. The intragranular phase comprises granules of
Lurasidone or salts thereof, and one or more of a binder, a disintegrant, a diluent, a
surfactant and less than 10% w/w of starch.
In another embodiment, the present invention includes a pharmaceutical composition
of Lurasidone or salts thereof comprising granules of Lurasidone or salts thereof, one
or more pharmaceutical excipient(s), and less than 10% w/w of starch, wherein the
composition is substantially free of any super-disintegrant.
In another embodiment of the present invention, a pharmaceutical composition of
Lurasidone or salts thereof, comprises: intra-granular phase comprising:
(a) from about 10 to 60% by weight Lurasidone or salts thereof;
(b) less than 10% w/w of starch;
(c) a binder, a disintegrant, a diluent and a surfactant,
wherein extra-granular phase of the composition is free of a binder, a disintegrant,
and a diluent.
In yet another embodiment, the present invention provides an immediate-release
pharmaceutical composition comprising Lurasidone or salts thereof, wherein 10-40%
of the granules are retained on the ASTM (American Society for Testing and
Materials) standards #60 mesh sieve. Preferably, 5-20% of the granules are retained
on the ASTM (American Society for Testing and Materials) standards #40 mesh
sieve.
The present invention also relates to process of preparing pharmaceutical
compositions of Lurasidone or salts thereof, wherein the process utilizes an aqueous
15
L H I O 5 - G 7 - 2 Q 1 7 17 : 0-0
and /or non-aqueous medium, a quantity of one or more surfactants sufficient to
dissolve or suspend said active ingredient uniformly throughout the medium and
other manufacturing additives as in to the art.
The medium may include granulating-binding agents such as gelatin; natural gums
such as acacia, tragacanth; starches, sodium alginate, sugars, polyvinylpyrrolidone;
cellulose derivatives such as hydroxypropylmethylcellulose, polyvinyloxoazolidones;
pharmaceutical fillers such as lactose, microcrystalline cellulose, dicalcium
phosphate, tricalcium phosphate, calcium sulfate, dextrose, mannitol, sucrose; tab
letting lubricants if needed such as calcium and magnesium stearate, stearic acid, talc,
sterotex (alkaline stearate). The components are granulated, the resulting granules are
dried, sieved and compressed into tablets or filled into capsules. Other oral dosage
forms may be similarly prepared such as chewable tablets, lozenges, troches,
sustained or delayed release products or suspensions.
The quantity of surfactant in the granulating mixture is sufficient to be non-toxic and
to support the active ingredient in aqueous and/or non-aqueous medium. Usually, this
means small quantities, such as less than 2% w/w based on total weight of the
composition.
As used herein, the term "starch" is used in broad sense to include not only starch but
its derivative also like corn starch, pregelatinized starch or other starch derivatives
thereof. Preferably, starch is used in an amount of less than 10% w/w by weight
based on total weight of the composition. More preferably, starch is used in an
amount of less than 6% by weight based on total weight of the composition.
Embodiments of the present invention relate to pharmaceutical compositions of
Lurasidone or its pharmaceutical^ acceptable salts, esters, solvates, polymorphs,
stereoisomers or mixtures thereof, one or more pharmaceutical excipient(s), and less
16
I 0 5 - 0 7 - 2 0 1 7 1 7 : 09
than 10% w/w of starch, wherein extra-granular phase of the composition is free of a
binder, a disintegrant, and a diluent and said composition releases more than 85% of
Lurasidone Hydrochloride within 30 minutes in diluted Mcilvaine buffer of pi-1 3.8.
In another embodiment of the invention, the solid oral pharmaceutical composition
comprising Lurasidone hydrochloride is prepared by any suitable method known in
the art such as direct compression, dry or wet granulation. The wet and dry processes
include, but are not limited to, wet granulation, dry granulation, dry blending, dry
mixing and direct compression. Other formulation techniques are also contemplated
within the scope of the present invention. Any pharmaceutically acceptable
granulating agent can be used for wet granulation. Preferable granulating solvents
include, but are not limited to, water, esters such as ethyl acetate; ketones such as
acetone; alcohols such as methanol, ethanol, isopropanol, butanol; dichloromethane,
chloroform, dimethyl acetamide (DMA), dimethyl sulfoxide (DMSO), ether, diethyl
ether and combinations thereof. Preferably, the granulating solvent used during wet
granulation is water.
In another embodiment of the invention, wet granulation can be performed using
Rapid mixer granulator, Fluid bed granulator, Planetary mixer and the like; dry
blending can be performed using V-blender or key blender; and dry granulation can
be performed using roller compacter or slugging techniques or by any other method
known in the art.
In another embodiment of the invention, there is provided a process for the
preparation of a pharmaceutical composition comprising Lurasidone or its
pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or
mixtures thereof, comprising the steps of a) Sifting the accurately weighed quantities
of active agent and one or more pharmaceutically acceptable excipient(s) through a
suitable sieve followed by mixing; b) Granulating the mixture of step a), with an
17
X 8 5 - 8 7 - 2-817 17 : ©O
binder solution (granulation in an aqueous or non-aqueous solvent); c) Drying the
granulated mass, optionally milling of the dried granules and mixed the sifted
granules; d) lubricated the sifted blend of step c); e) Compressing the lubricated
granules into tablets or filling in capsules.
In another embodiment of the invention, there is provided a pharmaceutical
composition comprising Lurasidone or its pharmaceutically acceptable salts, esters,
solvates, polymorphs, enantiomers or mixtures thereof, comprising the steps of: (a)
blending a mixture of Lurasidone hydrochloride and at least one pharmaceutically
acceptable excipient including a binder and/or a disintegrant; (b) optionally
compacting the blended material using roller compactor; (c) optionally milling the
compacted material; (d) blend from step (a) or milled material from step (c) was
lubricated with a suitable lubricant; (e) lubricated blend or granules from (d) was
compressed into tablets with a suitable tooling or filled in capsules.
In another embodiment of the invention, there is provided a process for preparation of
pharmaceutical composition comprising Lurasidone hydrochloride, wherein the
process is easily scalable at an industrial scale.
Various useful fillers or diluents include, but are not limited to microcrystalline
cellulose ("MCC"), sodium alginate, silicified MCC (e.g., PROSOLV™), microfine
cellulose, lactitol, cellulose acetate, kaolin, lactose, maltose, trehalose, starch,
pregelatinized starch, sucrose, mannitol, xylitol, sorbitol, dextrates, dextrin,
maltodextrin, compressible sugar, confectioners sugar, dextrose, polydextrose,
simethicone, fructose, calcium carbonate, calcium sulfate, calcium phosphate, dibasic
calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate,
magnesium oxide and mixtures thereof. Preferably, diluent is microcrystalline
cellulose (MCC) or lactose or any combination thereof. Preferably, the amount of
diluent is from about 1% to about 90.0% w/w.
18
I 0 5 - 0 7 - 2 0 1 ? 17:©Q
Various useful binders include, but are not limited to acacia, guar gum, alginic acid,
sodium alginate, dextrin, carbomer, maltodextrin, methylcellulose, ethyl cellulose,
hydroxyethyl cellulose, hydroxypropyl cellulose (HPC) (e.g., KLUCEL®),
hydroxypropyl methylcelulose (HPMC) (e.g., METHOCEL®), hydroxyethylmethyl
cellulose, carboxymethyl cellulose sodium, cottonseed oil, povidone (various grades
of KOLLIDON®, PLASDONE®), ceratonia, dextrose, polydextrose, starch, gelatin,
pregelatinized starch, hydrogenated vegetable oil type I, maltodextrin,
microcrystalline cellulose, polyethylene oxide, Polymethacrylates and mixtures
thereof. Binder can be present in powder form or as a dispersion or mixture of both.
Binder is optionally present in an amount from about 0 to about 10% by weight.
Various useful disintegrants include, but are not limited to croscarmellose sodium,
carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, povidone,
crospovidone, polacriilin potassium, sodium starch glycolate, alginic acid, sodium
alginate, calcium phosphate tribasic, colloidal silicon dioxide, docusate sodium, guar
gum, low substituted hydroxypropyl cellulose (L-HPC), magnesium aluminum
silicate, methylcellulose, microcrystalline cellulose, silicified microcrystalline
cellulose, starch and/or combinations thereof. Disintegrant is present in an amount
from about 0.5 to about 30% by weight, preferably about 2% to about 10% by weight
on the basis of the total weight of the composition.
Pharmaceutically acceptable lubricants include stearic acid, Zinc stearate, sucrose
stearate, sodium benzoate, hydrogenated vegetable oil type I, calcium stearate, adipic
acid, glyceryl palmitostearate, glycerine monostearate, medium-chain triglycerides,
sodium stearyl Fumarate, glyceryl behenate, sodium lauryl sulphate, sodium stearyl
fumarate, magnesium lauryl sulphate, magnesium stearate, polyethylene glycol.
Preferably, lubricant is magnesium stearate. The amount of lubricant is from about
0.1% to about 5% w/w.
19
I 0 5 - 9 7 - 2 0 1 . 7 17 : 0 0
Suitable surfactants include, but are not limited to both non-ionic and ionic
surfactants suitable for use in pharmaceutical dosage forms or those known to the
person skilled in the art. Ionic surfactants may include one or more of anionic,
cationic or zwitterionic surfactants. Surfactant used in the present invention includes,
but not limited to, polyoxyethylene alkylaryl ethers such as polyoxyethylene Iauryl
ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether; polyethylene glycol
(PEG) fatty acid esters such as PEG monolaurate, PEG dilaurate, PEG distearate,
PEG dioleate; polyoxyethylene sorbitan fatty acid ester such as Polysorbate 40,
polysorbate 60, polysorbate 80; sorbitan fatty acid mono esters such as sorbitan
monolaurate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate,
polyoxyethylene castor oil derivatives such as polyoxyl castor oil, polyoxyl
hydrogenated castor oil, sodium Iauryl sulphate and the like used either alone or in
combination thereof. The amount of surfactant present in the pharmaceutical
composition ranges from about 0.1% to about 25% by total weight of the
composition. Preferable less than 2% w/w by total weight of the composition.
Suitable glidants include, but are not limited to, calcium silicate, magnesium silicate,
magnesium trisilicate, stearic acid and its derivatives or esters like magnesium
stearate, calcium stearate and sodium stearate and the corresponding esters such as
sodium stearyl fumarate; talc and colloidal silicon dioxide, tribasic calcium
phosphate, starch or mixtures thereof. Preferably, the amount of glidant is from about
0 to about 10.0% w/w.
The invention further provides a method of treating Schizophrenia, Bipolar disorder
or Senile dementia in a patient comprising administering to said subject a
pharmaceutical composition comprising Lurasidone or salts thereof and one or more
pharmaceutical acceptable excipients.
20
Other excipient/carrier materials (such as anti-adherents, solubilizer, stabilizer,
colorants, flavors, sweeteners and preservatives) that are known in the pharmaceutical
art may be included in composition of the present invention,
The solid 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 Pharmacopoeial 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)Ei-in(R,-Tl)2]-0*5- 100}
Two dissolution profiles are considered similar when the f2 value is equal to or
greater than 50.
In another embodiment, pharmaceutical composition of the present invention exhibits
more than 85% of drug release within 30 minutes in 900 ml of 3.8 Mcilvaine Buffer
using a USP II apparatus (paddle) at a temperature of37±0.5°C and a rotation speed
of 50 revolutions per minute.
In another embodiment, solid oral pharmaceutical composition of the present
invention particularly tablet dosage form of present invention may be packaged in
HDPE bottles or blister packs. HDPE bottles may optionally contain desiccants.
21
LHI 0 5 - 0 7 - 2 0 1 7 17:OO
Having described the invention with reference to certain preferred embodiments,
other embodiments will become apparent to one skilled in the art from consideration
of the specification. The invention is further defined by reference to the following
examples describing in detail method for the preparation and testing of
Eslicarbazepine acetate pharmaceutical composition. It will be apparent to those
skilled in the art that many modifications, both to materials and methods, may be
practiced without departing from the scope of the invention. Following examples are
set out to illustrate the invention and do not limit the scope of the present invention.
EXAMPLES
Example 1
Lurasidone Hydrochloride tablet dosage form was prepared by wet granulation process
by using formula as given in Table I:
TABLE 1
Sr. No. Ingredient Quantity/Tablet(mg)
Intragranular Phase
1.
2.
3.
4.
5.
6.
Lurasidone hydrochloride
Mannitol/Lactose
Starch
Croscarmellose Sodium
Poloxamer
Hydroxypropyl methyl
cellulose
40.00
96.00
8.00
8.00
2.00
4.00
Extragranular Phase
7.
8.
Magnesium Stearate
Film Coating
Total
2.00
4.00
164.00
Procedure:
The processing steps involved in the manufacturing of tablet dosage form are given
below:
1. Lurasidone Hydrochloride, Lactose/mannitol, Starch, Croscarmellose
sodium were sifted through a suitable sieve.
2. The sifted blend was placed in a rapid mixer granulator and mixed for a
suitable time.
22
I O S - 0 7 - 2 0 1 7 17 : 00
3. This blend was granulated by Poloxamer and HPMC binder solution in
purified water.
4. The granules were dried in a fluidized bed dryer.
5. Granules obtained were lubricated with magnesium stearate and compressed
into tablets with a suitable tooling and the tablets were optionally coated with
commercially available film coating solutions.
Example 2
Lurasidone Hydrochloride tablet dosage form was prepared by dry granulation
process by using formula as given in Table 2:
TABLE 2
Sr. No. Ingredient Quantity/Tablet (mg)
Intragranular Phase
1.
• 2 .
3.
4.
5.
6.
Lurasidone hydrochloride
Mannitol/Lactose
Starch
Croscarmellose Sodium
Poloxamer
Hydroxypropyl methyl
cellulose
40.00
96.00
8.00
8.00
2.00
4.00
Extragranular Phase
7.
8.
Magnesium Stearate
Film Coating
Total
2.00
4.00
164.00
Procedure:
1. Lurasidone Hydrochloride, Lactose/Mannitol, Starch, Croscarmellose
Sodium, Poloxamer and Hydroxypropyl methyl cellulose were sifted
through a suitable sieve.
2. The sifted blend was compacted to prepare slugs. Slugs obtained were
milled to prepare granules.
3. The granules were screened using suitable sieve and lubricated with
Magnesium stearate and compressed into tablets with a suitable tooling
23
T Q 5 - 0 7 - - 2 0 1 7 17 -GO
and the tablets were coated with commercially available film coating
solutions.
Example 3
The characteristic properties of the present formulation can be demonstrated by
showing the dissolution profile of the product. The dissolution of the active
ingredient may be determined using standard procedures well known to those skilled
in the art (e.g. the dissolution test procedures, such as the Rotating Basket Method
(Apparatus I) or Paddle Method (Apparatus II), disclosed in the U.S. Pharmacopeia
(USP).
For present formulation, the dissolution profile is determined by using Diluted
Mcllvaine buffer, pH 3.8, at a Paddle (USP Type II) rotation speed of 50 rpm, and
900 mL of dissolution medium.
The dissolution profile of tablet dosage form prepared using quantitative composition
as given in Table 1 was measured in 900 ml of 3.8 Mcllvaine Buffer using a USP II
apparatus (paddle) at a temperature of 37±0.5°C and a rotation speed of 50
revolutions per minute. The dissolution test was conducted on the reference
formulation Latuda® Tablets in comparison to a tablet dosage form as given in
Example 1. The dissolution data is provided in Table 3.
TABLE 3
Time point
(min.)
5
10
15
20
30
% dru
Reference
66
92
97
99
100
g released
Example I
67
89
95
97
99
Since, both commercially available Latuda® Tablets and tablet dosage form prepared
using quantitative composition as given in Table 1 exhibited more than 85% of drug
release within 30 minutes, dissolution profiles of the two formulations were found to
be similar.
While this invention has been described in detail with reference to certain preferred
embodiments, it should be appreciated that the present invention is not limited to
those precise embodiments. Rather, in view of the present disclosure, which describes
the current best mode for practicing the invention, many modifications and variations
would present themselves to those skilled in the art without departing from the scope,
and spirit of this invention.

WE CLAIM:
1. A solid oral pharmaceutical composition comprising:
a. from about 10 to 60% by weight Lurasidone or its pharmaceutical^
acceptable salts;
b. less than 10% w/w of starch
c. from about 0.1% to 2.0% by weight of one or more surfactant;
wherein the extragranular phase of the composition is free of any excipient selected
from the group consisting of a binder, disintegrant and/or diluent.
2. The solid oral pharmaceutical composition as claimed in claim 1, wherein the
pharmaceutical^ acceptable excipient are selected from binder, diluent,
disintegrant, lubricant, surfactant, wetting agent, glidant, color, sweetener,
film formers and combinations thereof or mixtures thereof.
3. The solid oral pharmaceutical composition as claimed in claim 1, wherein the
composition is in the form of granules, tablets, capsules, caplets, and mini
tablets.
4. The solid oral pharmaceutical composition as claimed in claim 1, wherein the
composition comprises about 10 mg to about 160 mg of lurasidone
hydrochloride.
5. The solid oral pharmaceutical composition as claimed in claim 2, wherein the
one or more diluents comprise mannitol, lactose, microcrystalline cellulose,
silicified MCC, micro fine cellulose, starch, sorbitol, dextrates, dextrin,
maltodextrin, dextrose, calcium carbonate, calcium sulfate, dibasic calcium
phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate and
magnesium oxide.
6. The solid oral pharmaceutical composition as claimed in claim 2, wherein one
or more disintegrant comprises pregelatinized starch, sodium starch glycolate,
crospovidone, croscarmellose sodium, microcrystalline cellulose and
polacrilin potassium.
7. The solid oral pharmaceutical composition as claimed in claim 2, wherein one
or more binder comprises acacia, guar gum, alginic acid, dextrin,
maltodextrin, methylcellulose, ethyl cellulose, hydroxyethyl cellulose,
hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl
cellulose sodium and starch.
8. The solid oral pharmaceutical composition as claimed in claim 1, wherein one
or more surfactant comprises docusate sodium, poloxamer, sodium lauryl
sulphate, polysorbate and combination thereof.
9. A process for the preparation of a solid oral pharmaceutical composition
comprising Lurasidone or pharmaceutical^ acceptable salts thereof, wherein
the process comprises
a. sifting the accurately weighed quantities of Lurasidone
hydrochloride and one or more pharmaceutical^ acceptable
excipients through a suitable sieve followed by mixing.
b. granulating the mix of step (i) with aqueous solution of a binder
and/or surfactant.
c. drying the granulated mass at room temperature and sifting
through a suitable sieve.
d. prelubricating the sifted blend of step (iii) with sifted extragranular
material followed by lubrication with sifted lubricant(s) and
e. compressing the lubricated granules into tablets.
10. A solid oral pharmaceutical composition, comprising:
a. from about 10 to 60% by weight Lurasidone or its pharmaceutically
acceptable salts;
b. from about 30.0 to 96.0% by weight of one or more diluents;
c. from about 1.0% to 8.0% by weight of one or more binders;
d. from about 0.1 % to 2.0%) by weight of one or more surfactant;
wherein the extragranular phase of the composition is free of any excipient selected
from the group consisting of a binder, disintegrant and/or diluent.