FIELD OF THE INVENTION
The invention pertains to high drug load pharmaceutical compositions comprising an
anticonvulsant drug or its pharmaceutical!;/ acceptable salts, esters, solvates,
polymorphs, enantiomers or mixtures thereof. The present invention also relates to the
process of preparing high drug load pharmaceutical compositions by extrusionspheronization
technique.
BACKGROUND OF THE INVENTION ..
Eslicarbazepine (ESL) is a voltage-gated sodium channel blocker, an anticonvulsant
drug indicated for the treatment of partial-onset seizures as monotherapy or as an
adjunctive therapy. Eslicarbazepine acetate is a prodrug of Eslicarbazepine and is
chemically known as (5S)-5-hydroxy-5,6-dihydrobenzo[b]|T|benzazepine-l Icarboxamide.
It is structurally represented by the following formula:
Eslicarbazepine acetate is commercially marketed in Europe and the US as Zebinix®
and Aptiom® Tablets 200, 400, 600 and 800 mg respectively. Inactive ingredients of
the approved tablet product in EU and US are povidone, croscarmellose sodium, and
magnesium stearate. Various formulations of Eslicarbazepine acetate are disclosed in
following patent publications:
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Patent number US 5,753,646 assigned to Bial-Portela discloses method of preparation
of substituted dihydrodibenz[b,f]azepines including Eslicarbazepine or its
pharmaceutically acceptable salts. The publication also relates to their pharmaceutical
properties in the treatment of some central and peripheric nervous system disorders.
Eslicarbazepine acetate is reported to be poorly soluble in water which leads to poor
dissolution and administration of a high dose of the drug in order to attain desired
therapeutic effect. Poor aqueous solubility, flowability, compressibility and high dose
of the drug also pose technical challenges to formulation scientist in development of a
suitable formulation with desired technical attributes.
Patent number US 8,372,431 assigned to Bial-Portela describes oral pharmaceutical
compositions of Eslicarbazepine acetate such as tablets or capsules and also discloses
method of preparing them using conventional granulation techniques.
Patent publication WO 2011/091 131 assigned to Dr. Reddy's Laboratories describes
manufacturing process for the preparation of Eslicarbazepine. This publication.
specifically relates to process for the preparation of Eslicarbazepine acetate and
intermediates and it also generically enlists various dosage forms of Eslicarbazepine.
US Patent publication No. US 2014/0302152 assigned to Bial-Portela discloses
granular pharmaceutical dosage form of Eslicarbazepine acetate with one or more
. . . . .*.. * **. • •
pharmaceutical^ acceptable excipients.
US Patent publication 2007/0196488 assigned toNovartis AG discloses oral controlled
release compositions of Eslicarbazepine with lipophilic or hydrophilic swellable
£ substance. This patent publication suggests use of median particle size in range of about
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20 to about 50 jam for the preparation of controlled release compositions of
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Although above mentioned prior arts disclose various dosage forms of Eslicarbazepine
acetate including immediate and controlled release dosage forms, they fail to teach the
manufacturing process or optimization parameters for obtaining a high drug load
pharmaceutical composition of Eslicarbazepine acetate produced by using extrusionspheronization
technique.
The development of a robust high drug load pharmaceutical composition is a challenge
in itself. A large particle size of a poorly water soluble drug and high drug load
pharmaceutical composition possess tableting challenges such as poor cohesion
properties in the blend and reduced hardness. Therefore, there is a need of an alternative
formulation technique that can subside as well as overcome these problems for the
preparation of a desired dosage form.
One of the techniques to produce multi-particulate systems is extrusion followed by
spheronization. Extrusion-spheronization is a technique used for the preparation of
pharmaceuticals in the form of beads or spheroids or pellets of size ranging from about
0.5-2.0 mm in diameter. Pharmaceutical composition produced by using extrusionspheronization
ranges from barely shaped irregular particles with physical properties
similar to a conventional granulation to very spherical particles having properties that
are drastically different.
The present inventors have developed an alternate high drug load dosage form of
Eslicarbazepine acetate by using simple, dust free, reproducible, and commercially
viable process for attaining high spherocity, free flowing spheres so as to obtain
desirable physico-chemical properties, dissolution, stability and bioequivalence
complying with global health and medicine regulatory agencies.
4
OBJECTS AND SUMMARY OF THE INVENTION
It is a principal object of the present invention to provide a high drug load
pharmaceutical composition comprising Eslicarbazepine or its pharmaceutical ly
acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof with one
or more pharmaceutical ly acceptable excipients.
It is yet another object of the present invention to provide a process for the preparation
of high drug load pharmaceutical composition comprising Eslicarbazepine or its
pharmaceutical ly acceptable salts, esters, solvates, polymorphs, enantiomers or
mixtures thereof.
It is another object of the present invention to provide a high drug load solid oral
pharmaceutical composition comprising Eslicarbazepine or its pharmaceutical ly
acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, present
in an amount from about 40% to about 90% by weight with respect to total weight of
composition.
It is still another object of the present invention to provide a high drug load solid
pharmaceutical composition comprising Eslicarbazepine or its pharmaceutical ly
acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof,.
comprising at least one or more pharmaceutical^ acceptable excipients like diluent.
binder, disintegrant, glidant, lubricant, surfactant, wetting agent, polymer, solubilizer,
stabilizer, sweetener, flavoring agent, coloring agent and the like.
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 particular embodiments hereinafter described.
One embodiment of the present invention discloses, a high drug load pharmaceutical
composition comprising Eslicarbazepine or its pharmaceutical^ acceptable salts,
5
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esters, solvates, polymorphs, enantiomers or mixtures thereof prepared by using
extrusion-spheronization technique.
Another embodiment of the present invention relates to immediate release high drug
load pharmaceutical composition comprising Eslicarbazepine or its pharmaceutical!)'
acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof
prepared by using extrusion-spheronization technique.
Another embodiment of the present invention relates to high drug load modifiedrelease
or extended- release or delayed-release or controlled release or sustainedrelease
or combinations thereof, pharmaceutical composition comprising
Eslicarbazepine or its pharmaceutical^ acceptable salts, esters, solvates, polymorphs,
enantiomers or mixtures thereof, prepared by using extrusion-spheronization
technique.
Another embodiment of the present invention relates to high drug load pharmaceutical
composition of Eslicarbazepine or its pharmaceutical^ acceptable salts, esters,
solvates, polymorphs, enantiomers or mixtures thereof, comprising both immediate
release and modified-release component wherein the composition is prepared by using
extrusion-spheronization technique and the immediate and/ or modified-release
component is incorporated in core or coating.
Yet another" embodiment of the present invention relates to, a high drug load
pharmaceutical composition comprising Eslicarbazepine or its pharmaceutically
acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof
prepared by using extrusion-spheronization technique, wherein the said-pharmaceutical
composition is an oral composition comprising a matrix or a reservoir system.
6
/
Another embodiment of the present invention relates to a process for preparing cores
or granules of Eslicarbazepine or its pharmaceutical ly acceptable salts, esters, solvates,
polymorphs, enantiomers or mixtures thereof, the said cores
comprising: Eslicarbazepine or its pharmaceutical ly acceptable salt in an amount
greater than about 40% by weight, at least one binder, at least one
plasticizer, optionally a diluent or filler wherein the composition is prepared by a
process comprising (a) mixing of the ingredients, (b) granulating the mixture using
high shear granulator , (c) conveying the obtained wet mass through an extruder,
equipped with two counter-rotating rollers that either turn at similar or differential
speed, (d) spheronization of the rods obtained in step (c) and (e) optionally coating the
spheroids obtained in step (d).
In yet another embodiment, the present invention relates to a high drug load
pharmaceutical composition comprising Eslicarbazepine or its pharmaceutical ly
acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof,
wherein the particle size of Eslicarbazepine acetate is D90 less than 200 |im.
In accordance with yet another embodiment, the present invention relates to a high drug
load pharmaceutical composition of Eslicarbazepine or its pharmaceutical^ acceptable
salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, produced by using
extrusion-spheronization technique, wherein the composition is substantially free from
other polymorphic forms.
In accordance with still another embodiment the present invention relates to a method
of using the high drug load, pharmaceutical composition comprising spheronized
pellets of Eslicarbazepine acetate in the treatment of partial-onset seizures as
monotherapy or adjunctive therapy.
7
DESCRIPTION OF THE INVENTION
The present invention can be fully understood by description of detailed embodiments
and examples that follow them.
The present invention relates to high drug load pharmaceutical compositions
comprising Eslicarbazepine or its pharmaceutically acceptable salts, esters^ solvates.
polymorphs, enantiomers or mixtures with one or more pharmaceutically acceptable
excipients.
One embodiment of the present invention relates to a process for the preparation of
high drug load pharmaceutical composition comprising Eslicarbazepine or its
pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or
mixtures thereof.
As used in this application, the singular forms "a'5, "an", and "the" include plural
references unless the context clearly defines otherwise. Thus, for example, a reference
to "pharmaceutical composition" includes one or more dosage forms, and/ or
formulations and/or compositions which will become apparent to those persons skilled
in the art upon reading this disclosure and so forth.
The term "composition", as in pharmaceutical composition or "formulation" or
"dosage form" are used interchangeably and are specified to encompass a drug product
comprising Eslicarbazepine or its pharmaceutically acceptable salts, esters, solvates,
polymorphs, enantiomers or mixtures thereof, and other pharmaceutically-acceptable
excipients.
The term "high drug load" as used in the present invention, pertains to about 40% to
about 90% by weight of Eslicarbazepine or its pharmaceutically acceptable salts, esters,
solvates, polymorphs, enantiomers or mixtures thereof, based on total weight of the
composition.
8
The term "excipient" means a pharmacologically in-active component that can be subdivided
into various functional classifications, depending on the role it is intended to
play in the resultant formulation. For example diluents generally provide bulk to the
formulation, binders act as adhesive to 'bind together' powder or granules,
disintegrants are used for de-aggregation of solid dosage forms, others may include
glidants, surfactant, wetting agent, lubricant, polymers, solubilizer, stabilizers,
sweetener, flavoring agent, coloring agent and the like. The excipients used in
preparing pharmaceutical composition are generally safe and non-toxic for veterinary
as well as human pharmaceutical use. Excipients can be exemplified and are well
known to the skilled artisan in the relevant literature, for example in the Handbook of
Pharmaceutical Excipients.
The term "about" means ± approximately 20% of the indicated value, such that "about
10 percent" indicates approximately 08 to 12 %.
The term "pellets" or "beads" or "beadlets" or "spheroids" or "multi-particulates" are
used interchangeably and specified to encompass the said pharmaceutical composition.
The term "multi-particulates" as used herein means a plurality of discrete, or
aggregated, particles, pellets, beads, granules or mixture thereo/ irrespective of their
size, shape or morphology. Spheroids refer to almost round or spherical bulk particles
of a defined size produced using marumerization or spheronization.
The term "immediate release" refers to the release of drug primarily in stomach and
relatively faster as compared to release of a modified release pharmaceutical
composition. The term "extended-release" or "delayed-release" or "controlledrelease"
or "sustained-release" or "modifled-release" or "prolonged-release" can be
used interchangeably and refers to the release of drug throughout the gastrointestinal
tract wherein the release is dependent on the designing of the dosage form and the
excipients used therein. The release is relatively slower as compared to an immediate
release pharmaceutical composition.
9
The term "coat" or "coating" are used interchangeably and relate to the polymer coating
over the pharmaceutical composition such that it may provide immediate and / or
modified-release! The coating may be used to mask any unpleasant taste of the
ingredients of the particulate, including masking the taste of therapeutically active
compounds, granulating materials or any excipients. A coating may also be used to
provide for the controlled release of the therapeutically active compounds from the
particulate.
The term "extrusion-spheronization" refers to a multi-step and continuous solventbased
process used to make uniform spherical particles in form of beads or granules.
The technique presents the ability to include high drug load of active ingredient without
producing large size particles. The preliminary steps in the process are: (i) Dry-mixing
of ingredients to achieve a homogenous powder dispersion; (ii) Wet massing of step (i)
in a rapid-mixer granulator using binder solution to form granules of uniform size (iii)
Extrusion of wet granules of step (ii) to form uniformly rod-shaped
particles; (iv) Spheronization of uniformly rod-shaped particles of step (iii) to produce
spherical particles; (v) Screening to achieve the particles with narrow distribution of
size.
The pharmaceutical compositions of present invention comprise about 1 to about
1600mg of Eslicarbazepine" acetate, preferably about 200 to about 800mg of
Eslicarbazepine acetate. The pharmaceutical composition comprises Eslicarbazepine
acetate in the range of about 40% to about 90% by weight of Eslicarbazepine or its
pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or
mixtures thereof, based on total weight of the composition.
In another embodiment the high drug load pharmaceutical composition of the present
invention includes particle size of Eslicarbazepine acetate or its pharmaceutical^
acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, having
10
a particle size distribution such that D90 is less than about 200 |im, D50 is less than about
100 jam and D10 is less than about 50 Jim. The particle size of Eslicarbazepine acetate
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.
In another embodiment, the present invention includes a high drug load solid oral
pharmaceutical composition comprising from about 40% to about 90% by weight of
Eslicarbazepine acetate based on the total weight of the composition, wherein the
composition is substantially free of other polymorphic forms.
In another embodiment, the present invention incorporates a composition comprising
high drug load of active pharmaceutical ingredient, such as Eslicarbazepine or its
pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or
mixtures thereof and pharmaceutical^ acceptable excipients such as binders,
disintegrants, diluents, lubricating agents, sweeteners, surfactants, buffers, and/or
plasticizers and the like.
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,
2 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 present in an
amount from about 0.1 to about 70% w/w.
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Various useful disintegrants and/or super-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 or pre-gelatinized starch and/or combinations thereof
Disintegrant and/or super-disintegrants is present in an amount from about 0.1 to about
70%.
Surfactants or buffers can be used alternatively as systems to increase the solubility of
poorly water soluble drugs. Surfactants can be ionic or non-ionic surfactants.
Surfactants include, but are not limited to, cetylpyridinium chloride, docusate sodium,
glyceryl monoleate, macrogols, sodium lauryl sulfate, sorbitan esters or tocophersolan.
Buffering agents can be organic and inorganic acids and their salts. These include, but
are not limited, to fumaric acid, adipic acid, boric acid, calcium carbonate, calcium
lactate, tribasic calcium phosphate, citric acid monohydrate, glycine, maleic acid,
monosodium glutamate, potassium citrate, sodium acetate or sodium citrate.
Pharmaceutical^ 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 10%w/w.
Polymers are a class of excipients that may be classified as pl-I-dependent or pl-lindependent
polymers and are used for film coating or modified-release coating.
12
Various pH-dependent polymers used in the composition may include, acrylic acid
copolymers, sodium alginate, and sodium carboxymethyl cellulose, pl-l-independent
polymers may include, vinyl acetate/vinyl chloride copolymers, acrylate/methacrylate
copolymers, polyethylene oxide, stearyl alcohol, hydroxypropyl methylcellulose,
hydroxyethyl cellulose, hydroxypropyl cellulose, ethylcellulose, cellulose acetate,
sodium carboxymethyl. cellulose, methyl cellulose, beeswax, carnauba wax, cetyl
alcohol, hydrogenated vegetable oils, carrageenan, alginic acid and salts thereof. The
amount of polymer is from about 0% to about 30% w/w.
Another embodiment of the present invention relates to a high drug load
pharmaceutical composition comprising Eslicarbazepine or its pharmaceutically
acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, present
in amount from about 40% to about 90% by total weight of composition.
Another embodiment of the present invention relates to an immediate release high drug
load pharmaceutical composition comprising Eslicarbazepine or its pharmaceutical ly
acceptable salts, esters, solvates, polymorphs,, enantiomers or mixtures thereof,
prepared by using extrusion-spheronization technique.
Another embodiment of the_ present invention relates to a high drug load extendedrelease
or delayed-release or controlled-release or sustained-release or modifiedrelease
pharmaceutical composition comprising Eslicarbazepine or its
pharmaceutical ly acceptable salts, esters, solvates, polymorphs, enantiomers or
mixtures thereof, prepared by using extrusion-spheronization technique.
Another embodiment of the present invention relates to high drug load pharmaceutical
composition of Eslicarbazepine or, its pharmaceutical^ acceptable salts, esters,
solvates, polymorphs, enantiomers or mixtures thereof comprising both immediate
release arid modified release components, wherein the composition is prepared by
13
using extrusion-spheronization technique and the immediate and/ or modified-release
component is incorporated in core or coating.
Another embodiment of the present invention relates to a high drug load
pharmaceutical composition comprising Eslicarbazepine or its pharmaceutically
acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof,
prepared by using extrusion-spheronization technique, wherein the said pharmaceutical
composition is an oral composition in a matrix or a reservoir system.
Another embodiment of the present invention relates to a high drug load
pharmaceutical composition comprising Eslicarbazepine or its pharmaceutical ly
acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof
prepared by using extrusion-spheronization technique, wherein the said pharmaceutical
composition provides immediate release and / or extended-release or delayed-release
or controlled-release or sustained-release or modified-release and comprises a matrix
system such that the modified-release polymer is homogenously dispersed in the core.
Another embodiment of the present invention relates to a high drug load
pharmaceutical composition comprising Eslicarbazepine or its pharmaceutical ly
acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof
prepared by using extrusion-spheronization technique, wherein the said pharmaceutical
gj composition provides immediate release and / or extended-release or delayed-release
or controlled-release or sustained-release or modified-release and comprises a reservoir
system such that the modified-release polymer is coated over the core.
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g pharmaceutical composition comprising Eslicarbazepine or its pharmaceutical ly
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prepared by using extrusion-spheronization technique wherein the said pharmaceutical
14
composition provides immediate release and / or extended-release or delayed-release
or controlled-release or sustained-release or modified-release and comprises beads
based on matrix system as well as reservoir system.
Another embodiment of the present invention relates to a process for preparing cores
or granules of Eslicarbazepine or its pharmaceutically acceptable salts, esters, solvates.
polymorphs, enantiomers or mixtures thereof, the said cores comprising:
Eslicarbazepine or its pharmaceutically acceptable salt in an amount greater than about
40% by weight, at least one binder, at least one plasticizer, optionally a diluent or
filler wherein the composition is prepared by a process comprising (a) mixing of the
ingredients, (b) granulating the mixture using high shear granulator, (c) conveying the
obtained wet mass through an extruder, equipped with two counter-rotating rollers that
either turn at similar or differential speed, (d) spheronization of the rods obtained in
step (c) and (e) optionally coating the spheroids obtained in step (d) using film coat or
modified-release coating.
The compositions of the invention may also contain one or more active ingredients in
addition to the Eslicarbazepine acetate. The additional active ingredient may be another
antipsychotic, anticonvulsant (such as topiramate, lamotrigine, oxcarbazepine or like).
antiepileptic, anti-diabetic (such as metformin, gliclazide or like), oral contraceptives
(such as microgynon or like) and/or HMG CoA" reductase inhibitors (such "as*
simvastatin, atorvastatin or like) compound including dibenz[b,f|azepine-5-
carboxamide derivatives, or it may be an active ingredient having a different
therapeutic activity like vitamins, antibiotics, cardiovascular agents, NSAIDs and like.
The embodiments of present invention also relate to high drug load solid oral
pharmaceutical composition of Eslicarbazepine or its pharmaceutically acceptable
salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, and at least one or
more pharmaceutically acceptable excipient, wherein the composition exhibits at least
15
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20% of drug release within 15 minutes in 1000 ml of Acetate Buffer, pH 4.5 (Office
of Generic Drugs dissolution database) using USP II apparatus (Paddle) at a
temperature of 37±0.5°C and a rotation speed of 100 revolutions per minute.
The embodiments of present invention also relate to high drug load solid oral
pharmaceutical composition of Eslicarbazepine or its pharmaceutically acceptable
salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, and at least one or
more pharmaceutically acceptable excipient, wherein the composition exhibits at least
40%) of drug release within 30 minutes in 1000 ml of Acetate Buffer, pH 4.5 (Office
of Generic Drugs dissolution database) using USP II apparatus (Paddle) at a
temperature of 37±0.5°C and a rotation speed of 100 revolutions per minute.
The following non-limiting examples illustrate specific embodiments of the present
invention. They are, however, not intended'to be limiting the scope of the present
invention in any way.
Example 1-3
S. No.
1.
'2.
3.
4.
5.
6.
7.
8.
9.
Ingredients
Eslicarbazepine
HPMC
Sodium Starch Glycolate
Microcrystalline cellulose
Sodium Lauryl Sulfate
Magnesium stearate
Purified Water
pH-dependent /
pH-independent polymer (core)
pH-dependent /
pH-independent polymer (coat)
Quantity % w/w
1
50-85%
0.5-10%
0.1-5%
10-40%
0-5%
0.1-2%
q.s
-
-
2
50-85%
0.5-10%..
0.1-5%
10-20%
0-5%
0.1-2%
q.s
0-20%
-
3
50-85%
0.5-10%
0.1-5%
10-20%
0-5%
0.1-2%
q.s
-
0-20%
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Preparation Method:
Eslicarbazepine acetate, microcrystalline cellulose, sodium starch glycolate and
sodium lauryl were sifted. The sifted blend was dry-mixed using rapid-mixer
granulator for 5 minutes. The binder and/ or polymer solution was prepared using water
as granulating liquid. The dry mix was granulated using binder and/or polymer
solution. Wet granules from were extruded using roller- extruder with the desired sieve
to obtain rod-shaped particles. The rod-shaped particles were spheronized using
spheronizer at optimized rotations-per-minute. The beads obtained were dried using
fluid bed dryer (FBD) with optimized parameters. The beads were then optionally
coated (film coat or modified coat) using and filled into capsules of appropriate size.
The dissolution profile of a high drug load of a pharmaceutical composition prepared
using quantitative composition as given in Example 1 was measured in 1000 ml of
Acetate Buffer, pH 4.5 (Office of Generic Drugs dissolution database) using a USP II
apparatus (Paddle) at a temperature of 37±0.5°C and a rotation speed of 100 revolutions
per minute. Dosage forms prepared as per present invention exhibited at least 40% drug
release in 30 minutes.
Many modifications of this invention can be made without departing from its spirit and
scope, as will be evident to those skilled in the art. The specific embodiments described
herein are provided by way of example only, and the invention is to be limited only by
the terms of the appended claims, along with the full scope of equivalents to which
such claims are entitled.

WE CLAIM:
1. A high drug load solid oral pharmaceutical composition comprising
Eslicarbazepine or its pharmaceutically acceptable salts, esters, solvates,
polymorphs, enantiomers or mixtures thereof, and one or more
pharmaceutical^ acceptable excipient, wherein the composition is prepared by
using extrusion-spheronization technique.
2. An immediate release high.drug load solid oral pharmaceutical composition
comprising Eslicarbazepine or its pharmaceutical^ acceptable salts, esters,
solvates, polymorphs, enantiomers or mixtures thereof, wherein the
pharmaceutical composition is prepared using extrusion-spheronization
technique.
3. A modified release high drug load solid oral pharmaceutical composition
comprising Eslicarbazepine or its pharmaceutical ly acceptable salts, esters,
solvates, polymorphs, . enantiomers or mixtures thereof, wherein the
pharmaceutical composition is prepared using extrusion-spheronization
technique.
4. A high drug load solid oral pharmaceutical composition of Eslicarbazepine or
its pharmaceutical^ acceptable salts, esters, solvates, polymorphs, enantiomers
or mixtures thereof prepared by using extrusion-spheronization technique,
wherein the pharmaceutical composition comprises both immediate release and
modified-release components.
5. A process of preparing high drug load solid oral pharmaceutical composition
of Eslicarbazepine or its pharmaceutical^ acceptable salts, esters, solvates,
polymorphs, enantiomers or mixtures thereof, wherein the process comprises
the steps of:
(a) dry mixing about 40% to about 90% of Eslicarbazepine acetate and
pharmaceutically acceptable excipients to form a homogenous dispersion,
(b) granulating the homogenous dispersion using binder solution to form a wet
mass,
(c) extruding the wet mass to form cylindrical structures,
(d) spheronizing the cylindrical structures to form beads,
(e) drying the beads using fluidized-bed drying and optionally coating the beads
with a film coat or extended release coat.
6. A high drug load solid oral pharmaceutical composition of Eslicarbazepine or
its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers
or mixtures thereof as claimed in claim 1-5, wherein the pharmaceutical
composition comprises about 1 to about 1600mg of Eslicarbazepine acetate.
7. A high drug load solid oral pharmaceutical composition of Eslicarbazepine or
its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers
or mixtures thereof as claimed in claim 1-5, wherein the pharmaceutical
composition exhibits a dissolution rate of at least about 40% within 30 minutes
when tested in 1000 ml of acetate buffer medium in a USP apparatus 11 at 100
rpm.
8. A high drug load solid oral pharmaceutical composition of Eslicarbazepine or
its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers
or mixtures thereof as claimed in claim 1-5, wherein the pharmaceutical
composition exhibits a dissolution rate of at least 20% within 15 minutes when
tested in 1000 ml of acetate buffer medium in a USP apparatus II at 100 rpm.
9. A high drug load solid oral pharmaceutical composition of Eslicarbazepine or
its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers
or mixtures thereof as claimed in claim 1-5, wherein the pharmaceutical
composition comprises a matrix system. (
10. A high drug load solid oral pharmaceutical composition of Eslicarbazepine or
its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers
or mixtures thereof as claimed in claim 1-5, wherein the pharmaceutical
composition comprises a reservoir system.
or mixtures thereof as claimed in claim 1-5, wherein the pharmaceutical
composition comprises a reservoir system.