Specification
FIELD OF THE INVENTION
The present invention relates to solid oral pharmaceutical composition comprising (S)-
lO-acetoxy-10,1 l-dihydro-5H-dibenzo[b,f|azepine-5-carboxamide (Eslicarbazepine)
or its pharmaceutically acceptable salts, solvates, esters, enantiomers, polymorphs or
mixtures thereof. In particular, but without restriction to the particular embodiments
hereinafter described in accordance with the best mode of practice, present invention
provides a solid oral pharmaceutical composition comprising Eslicarbazepine or its
pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or
mixtures thereof and a excipient and/or carrier wherein the said1 composition is prepared
by. using solid dispersion technique. The invention also relates to process for the
preparation of such compositions.
BACKGROUND OF THE INVENTION
Eslicarbazepine acetate is a voltage-gated sodium channel blocker which is used as an
anticonvulsant in the treatment of partial-onset seizures as monotherapy or adjunctive
therapy, epilepsy, affective disorders and neuropathic pain. Eslicarbazepine acetate is
chemically known as (S)-10-acetoxy-10,11 -dihydro-5H-dibenzo [b,f|azepine-5:
carboxamide, with the chemical structure as given below:
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Eslicarbazepine acetate is commercially available under the trade name APTIOM® in
200, 400, 600, and 800 mg tablets in US market for treatment of partial-onset seizures
as monotherapy or adjunctive therapy by Sunovion Pharms Inc. Marketed formulation
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contains inactive ingredients like povidone, croscarmellose sodium, and magnesium
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stearate. Following patent publications pertain to various formulations of
Eslicarbazepine acetate:
Eslicarbazepine was first disclosed in U.S. Patent No. 5,753,646, assigned to Bial-
Portela, which describes dihydrodibenzo[b,f|azepines derivatives including
Eslicarbazepine acetate or stereoisomer thereof. This patent publication also discloses
process for the preparation of substituted dihydrodibenz [b,f| azepines derivatives and
use in the treatment of some central and peripheric nervous system disorders.
As per Biopharmaceutics Classification System, Eslicarbazepine acetate is a class II
drug, accordingly is reported to be poorly soluble in water and is virtually undissolved
in the gastro intestinal tract. This relative insolubility of Eslicarbazepine acetate leads
to its less systemic absorption and accordingly requires administration of a high dose
of the drug.
Technical challenges associated with the development of Eslicarbazepine acetate
dosage form are poor aqueous solubility, poor flowability, poor compressibility and
high dose of the drug. Thus, it is challenging to a formulation scientist to develop a
suitable dosage form of Eslicarbazepine acetate with desired technical attributes.
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cc US Patent publication No. 2007/0196488 assigned to Novartis AG discloses oral a
z- controlled release compositions of Eslicarbazepine with lipophilic or hydrophilic
?T swellable substance. This patent publication suggests use of median particle size in
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range of about 20 to about 50 \LXX\ for the preparation of controlled release compositions
g „ of Eslicarbazepine.
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glyceride, vitamin E such as tocophersol; tocotrienols; polyethylene or
polyoxyethylene ester of hydroxy! stearic acid, polyoxylglycerides, polyethoxylated'
castor oil, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. HPC
EF, H.PC LF and HPC IR), hydroxypropyl methylcellulose (e.g. Methocel E3 and El 5
and Pharmacoat 645), hydroxypropyl methylcellulose acetate succinate' (HPMC AS).
hydroxypropyl methylcellulose phthalate (e.g. HPMCP-HP55), polyvinylpyrrolidone
(e.g. PVP 30K and PVP 90K), polyvinyl alcohol (PVA), polyvinyl acetate phthalate
(PVAP), copolyvidone (e.g. Kollidon VA 64), crospovidone (e.g. Kollidon CL),
methacrylic acid and ethylacrylate copolymer (e.g. Kollicoat ME), methacrylate acid
and methyl methacrylate copolymer (e.g. Eudragit LI00), polyethylene glycol (e.g.
PEG20K), DL lactide/glycolide copolymer (PDLG), poly DL-lactide (PDL), cellulose
acetate phthalate (CAP)., hypromellosc, such as methylcellulose USP, hypromellose
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2910, hypromellose 2906 and hypromellose 2208 (also known as Methocel K4M).
starch, pectin, pullulan, mannan, gelatin, gum arabic, a dextrin, a cyclodextrin, agar, a
polyoxysorbitan fatty acid ester, an alginate, aminoalkyl methacrylate copolymers (e.g.
Eudragit RL100, RL PO or RS PO), carbomer homopolymer Type A (e.g. Carbopol
971 P), carbomer homopolymer Type B (e.g. Carbopol 974P), sodium dodecyl sulfate,
d-alpha-tocopherol acid polyethylene glycol 1000 succinate (TPGS), polyvinyl
caprolactam-poly vinyl acetate-polyethylene glycol copolymer (Soluplus) and
poloxamers (e.g. Pluronics, Lutrol 68, Lutrol F127, Kolliphor) or any combinations
thereof Preferably, the carrier is PEG 6000.
Solvents include but are not limited to water, dipolar aprotic solvent, polyethylene
glycol, polyethyleneglycol ether, polyethyleneglycol derivative of a mono- or diglyceride,
buffers, water soluble organic solvents, organic solvents or any combination
thereof
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% which is present either in intra-granular or in extra-granular part of the
composition. Preferably, the amount of disintegrant is from about 0.5% to about 15%
w/w.
Various useful fillers or diluents/include, but are not limited to microcrystalline
cellulose ("MCC"), sodium alginate, silicified MCC (e:g., PROSOLV™), microfine
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cellulose, lactitol, cellulose acetate, kaolin, lactose, maltose, trehalose, starch.
pregelatinized starch, sucrose, mannitol, xylitol, sorbitol, dextrates, dextrin.
maltodextrin, compressible sugar, confectioner's sugar, dextrose, polydextrose, talc,
simethicone, fructose, calcium carbonate, calcium sulfate, calcium phosphate, dibasic
calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate,
magnesium oxide, inorganic salts and mixtures thereof. Preferably, diluent is
microcrystalline cellulose (MCC) or lactose or any combination thereof Preferably,
the amount of diluent is from about 0% to about 80.0% w/w.
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; h'ydrogenated 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 which is present either in intrargranular (dry
and/or dispersion) or in extra-granular part of the composition. Preferably-' the amount
of binder is from about 0.5% to about 15% w/w.
Pharmaceutical^ acceptable lubricants include stearic acid, zinc stearate, sucrose
?T stearate, sodium benzoate, hydrogenated vegetable oil type I, calcium stearate, adipic
acid, glyceryl palmitostearate, glycerine monostearate, medium-chain triglycerides,
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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. More preferably, the amount of lubricant is form about 0.25%
to about 2% w/w.
Surfactants or surface-active agents improve wettability of the dosage form and/or
enhance its dissolution. Surfactants contemplated in the present invention include, but
are not limited to, anionic surfactants, amphoteric surfactants, non-ionic surfactants and
macromolecular surfactants. Surfactant may constitute from about 0% to about 5% by
weight of 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.
Other 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. • . i
The pharmaceutical composition of the present invention can be used for treatment of
epilepsy, partial-onset seizures as a monotherapy or adjunctive therapy, affective
disorders, neuropathic pain, motor impairment, fibromyalgia, post-herpetic neuralgia,
bipolar disorder, schizoaffective disorders, attention disorders, anxiety disorders or any
other central and peripheric nervous system disorder.-
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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
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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.
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..
Example 1-6
Eslicarbazepine acetate tablets were prepared by using quantitative formula as given
in Table 1:
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Sr. No.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Ingredient
Eslicarbazepine acetate
Polyethylene Glycol
Polyvinylpyrrolidone K-30
Co povidone
Hydroxypropyl methylcellulose
Ethyl Cellulose
Polaxamer . !
Other Excipients
Lactose or Microcrystalline Cellulose
Sodium Starch Glycolate /
Croscarmellose sodium
HPMC
QTY/Tablet (%w/w)
1 2 3
40-95
0.1-20
-
-
-
..
-
-
0.1-20
-
-
-
-
-
-
0.1-20
-
-
-
0-10
0-15
0-10
4
-
-
-
0.1-20
-
5
-
-
-
-
0.1-20
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6
-
-
-
-
-
0.1-20
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12. Magnesium stearate 0.1-4
Preparation Method:
Examples 1-6 Solid Dispersion prepared by Solvent Evaporation Technique:
Eslicarbazepine acetate was dispersed in methylene chloride. This dispersion was
further added with a solution of polyethylene glycol and H.PMC dissolved in the
methylene chloride. The resulted solution was dried by using solvent evaporation
method. Dry product was mixed with microcrystalline cellulose, sodium starch.
glycolate. Blend was lubricated with magnesium stearate and was compressed into
tablets using suitable punches.
Examples 1-6 Solid Dispersion prepared by Hot Melt Extrusion Technique:
Sift all ingredients through suitable sieve. Mix all the sifted materials uniformly.
Add the above mixture in a hot melt extruder and collect the extrudate. Mill the
above extrudate and pass through desired sieve to get desired product. Compressed
into tablets or filled into capsules using suitable tools.
Examples 1-6 Solid Dispersion prepared by Co-Precipitation Technique:
Sift all ingredients through suitable sieve. Dissolve weighed quantity of
Eslicarbazepine acetate, carrier in alcohol with stirring. Add water to above solution
with stirring to form a precipitate. Dry the precipitate, mill and pass through the
desired sieve. Compressed into tablets or filled into capsules using suitable tools.
Example 7
Dissolution characteristics of the pharmaceutical composition
The standardized method and equipment for testing dissolution time is provided in
Office of Generic Drugs dissolution database. The dissolution profile of tablets dosage
form 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
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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 more
than 40% drug release in 30 minutes.
Example 8
Disintegration characteristics of the pharmaceutical composition
The standardized method and equipment for testing of disintegrating time is provided
in United State Pharmacopeia (USP). The formulations were tested according to the
said method. The disintegration test was conducted on the solid oral tablet dosage form
prepared as per quantitative composition as given in Example-1. Disintegration-time
was less than 10 minutes.
Example 9
Results: TABLE 2
Elements
Compressibility Index (%)
Hausner Ratio
Thickness (mm)
Friability (%)
Results
27.6
1.3
6.28
0.4
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 pharmaceutical composition comprising a solid dispersion of Eslicarbazepine
or its pharmaceutically acceptable salts, esters, solvates, polymorphs,
enantiomers or mixtures thereof in a pharmaceutical^ acceptable carrier and
excipient.
2. The pharmaceutical composition as claimed in claim I, wherein the one or more
pharmaceutical^ acceptable carrier is selected from the group consisting of
copovidone, ethyl cellulose, hydroxypropyl methyl cellulose, polyethylene
glycol, and soluplus and a graft copolymer comprised of polyethylene glycol,
polyvinylcaprolactam and polyvinylacetate or a combination thereof.
3. The pharmaceutical composition as claimed in claim 1, wherein
pharmaceutical^ acceptable excipient is selected from one or more of a diluent;
binder, disintegrant, surfactant, glidant, lubricant or a combination thereof.
4: A solid dispersion pharmaceutical composition as claimed in claim I to 3,
wherein one or more disintegrant comprises pregelatinized starch, sodium
starch glycolate, crospovidone, croscarmellose sodium, microcrystalline
cellulose and polacrilin potassium.
5. A solid dispersion pharmaceutical composition as claimed in claim I to 3,
wherein one or more binder comprises acacia, guar gum, alginic acid, dextrin,
maltodextrin, methylceMulose, ethyl cellulose, hydroxyethyl cellulose,
hydroxypropyl cellulose, /hydroxypropyl methylceMulose, carboxymethyl
cellulose sodium and starch.
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6. A solid, dispersion pharmaceutical composition as claimed in claim I to 5,
/. wherein Eslicarbazepine ..or its pharmaceutical^ acceptable salts, esters.
solvates, polymorphs, enantiomers or mixtures thereof is present in an amount
ranging from about 100 mg to about 1200 mg.
7. A solid dispersion composition of Eslicarbazepine acetate, wherein extragranular
part of the composition is free of binder and/or disintegrant.
8. A pharmaceutical tablet composition comprising: a) about 30-95% w/w oF
Eslicarbazepine or its pharmaceutical!)/ acceptable salts; b) about 0.1-15%) w/w
of a disintegrant; c) about 0.1-5% w/w of a binder; d) about 0.1-10% w/w of a
diluent; e) about 0.1-10% w/w of a pharmaceutically acceptable carrier,
wherein the composition is prepared by using solid dispersion technique.
9. A process for the preparation of solid dispersion of Eslicarbazepine acetate,
wherein the process comprising dispersing Eslicarbazepine or its pharmaceutical ly
acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof in a
excipient and/or a carrier using one or more process selected from hot- melt, comelt
and congealing, and solvent evaporation techniques.
10. A pharmaceutical composition comprising a solid dispersion of Eslicarbazepine or
its pharmaceutical^ acceptable salts, esters, solvates, polymorphs, enantiomers or
-mixtures thereof in polyethylene glycol, wherein the 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 II at 100 rpm.