DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

PHARMACEUTICAL COMPOSITIONS OF ESLICARBAZEPINE AND PROCESS FOR PREPARATION THEREOF

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
THE WATER MARK BUILDING,
PLOT NO.11, SURVEY NO.9,
HITECH CITY, KONDAPUR,
HYDERABAD - 500 084,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes the invention and the manner in which it is to be performed.
FIELD OF THE INVENTION

The present invention relates to a solid pharmaceutical composition comprising eslicarbazepine or its pharmaceutically acceptable salt thereof as an active agent and pharmaceutically acceptable excipients and its preparation process and method of using the same.

BACKGROUND OF THE INVENTION

Epilepsy is defined as a chronic neurological condition characterized by recurrent, unprovoked seizures. Epilepsy is a group of neurological disorders characterized by epileptic seizures.

Epileptic seizures are divided fundamentally into two groups: partial and generalised. Partial seizures are those in which the discharge begins locally, and often remains localized. Generalised seizures involve the whole brain, including the reticular system, thus producing abnormal electrical activity throughout both hemispheres and immediate loss of consciousness.

Eslicarbazepine acetate is a voltage-gated sodium channel blocker, a third-generation member of the first-line dibenz[b,f]azepine antiepileptic drugs represented by carbamazepine (first-generation) and oxcarbazepine (second-generation) providing anticonvulsant effect and used in the treatment of partial-onset seizures as monotherapy or adjunctive therapy. Eslicarbazepine acetate is chemically known as (S)-10-acetoxy-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carboxamide and is represented by the following formula:

As per Biopharmaceutics classification system, Eslicarbazepine is a class II drug and has low aqueous solubility and high permeability compound and poses technical challenges in the formulation development.

Eslicarbazepine acetate is commercially marketed as APTIOM® by Sunovion Pharmaceuticals as an immediate release tablet in strengths of 200, 400, 600, and 800 mg. APTIOM® tablets contain Eslicarbazepine acetate along with inactive ingredients as povidone, croscarmellose sodium and magnesium stearate.

Following patent publications pertain to various formulations of Eslicarbazepine acetate:
U.S. Patent No. 5,753,646 describes dihydrodibenzo [b,f] azepines derivatives including Eslicarbazepine acetate, process for the preparation thereof and compositions of eslicarbazepine with inert pharmaceutically acceptable carriers.

US Patent publication No. 2007/0196488 discloses oral controlled release compositions of Eslicarbazepine with median particle size in the range of about 20 to about 50 µm with lipophilic or hydrophilic swellable substance.

US Patent publication No. 2014/0302152 discloses granular pharmaceutical dosage form of Eslicarbazepine acetate with one or more pharmaceutically acceptable excipients.

US Patent No. 8,372,431 discloses pharmaceutical composition of Eslicarbazepine acetate prepared by granulation process wherein disintegrant is essentially present in both intra-granular as well as extra-granular portion of the composition in equal proportion.

US Patent publication No. 2018/0280307 discloses solid oral pharmaceutical composition comprising Eslicarbazepine, wherein the extra-granular part of the composition is free of a disintegrant.

Indian Patent publication No. 201641037212 discloses pharmaceutical composition of Eslicarbazepine with improved dissolution properties prepared by dry granulation technique.

Indian Patent publication No. 201611000599 and 20111000598 discloses pharmaceutical composition of Eslicarbazepine acetate prepared by using Solid dispersion technique and extrusion-spheronization technique respectively.

International Patent publication No. WO2020130960 discloses pharmaceutical composition of Eslicarbazepine acetate prepared by dry granulation technique.

The prior art discloses complex approaches for formulating Eslicarbazepine acetate into suitable dosage form like use of a) specific excipients povidone as binder, croscarmellose sodium as disintegrant b) half of disintegrant in intra-granular part and half of disintegrant in extra-granular part, c) half of binder in intra-granular part in powder form and half of binder in liquid form. Thus, there is a need of preparation of alternate dosage form of Eslicarbazepine acetate manufactured by simple, reproducible and commercially viable process at industrial scale with desirable technical formulation attributes such as dissolution, stability and bioequivalence.

The inventors of the present invention have developed solid pharmaceutical composition of Eslicarbazepine or its pharmaceutically acceptable salts thereof and unexpectedly found that said composition have improved stability and dissolution profile coupled with simple manufacture process at industrial scale and it is bioequivalence to commercially available counterpart tablets (APTIOM®).

SUMMARY OF THE INVENTION

In one aspect, the invention relates to a solid pharmaceutical composition comprising Eslicarbazepine or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof with one or more pharmaceutically acceptable excipient.

In another aspect, an invention provides a solid pharmaceutical composition comprising:
a) 80-90% w/w of Eslicarbazepine or its pharmaceutically acceptable salt thereof, wherein particles of eslicarbazepine or a salt thereof have a D90 equal to or less than 30µm;
b) 2-8% w/w of povidone;
c) 5-20% w/w of disintegrant selected from sodium starch glycolate, crospovidone or a combination thereof;
d) 0.1-1% w/w of colloidal silicon dioxide;
e) 0.8-2.0% w/w of magnesium stearate;
Wherein at least 80% of eslicarbazepine dissolves within 45 minutes in a 1000ml of pH 4.5 acetate buffer at a temperature of 37±0.5°C using a USP apparatus-2 at a paddle rotation of about 100 rpm.

In another aspect, an invention provides a solid pharmaceutical composition comprising:
a) 200-800mg of Eslicarbazepine or its pharmaceutically acceptable salt thereof, wherein particles of eslicarbazepine or a salt thereof have a D90 equal to or less than 30µm;
b) 08-50mg of povidone;
c) 15-85mg of disintegrant selected from sodium starch glycolate, crospovidone or a combination thereof;
Wherein compositions contains less than 0.15% of the individual impurity and not more than 1.5% of total impurities by weight relative to eslicarbazepine when measured by HPLC after storage for 6 months at 40oC/75% relative humidity.

In another aspect, an invention provides a solid pharmaceutical composition comprising:
a) 80-90% w/w of Eslicarbazepine or its pharmaceutically acceptable salt thereof, wherein particles of eslicarbazepine or a salt thereof have a D90 equal to or less than 30µm;
b) 2-8% w/w of povidone;
c) 5-20% w/w of disintegrant selected from sodium starch glycolate, crospovidone or a combination thereof;
Wherein the weight ratio of eslicarbazepine or its pharmaceutically acceptable salt thereof to povidone is about 1:0.04 to 1:0.06.

In another aspect, an invention provides a solid pharmaceutical composition comprising:
a) 80-90% w/w of Eslicarbazepine or its pharmaceutically acceptable salt thereof, wherein particles of eslicarbazepine or a salt thereof have a D90 equal to or less than 25µm;
b) 2-8% w/w of povidone;
c) 5-20% w/w of disintegrant in a weight ratio of sodium starch glycolate to crospovidone is about 0.6:1 to 1:0.6;
d) 0.1-1% w/w of colloidal silicon dioxide;
e) 0.8-2.0% w/w of magnesium stearate;
Wherein at least 80% of eslicarbazepine dissolves within 45 minutes in a 1000ml of pH 4.5 acetate buffer at a temperature of 37±0.5°C using a USP apparatus-2 at a paddle rotation of about 100 rpm.

In another aspect, an invention provides a solid pharmaceutical composition comprising:
a) 200-800mg of Eslicarbazepine or its pharmaceutically acceptable salt thereof, wherein particles of eslicarbazepine or a salt thereof have a D90 equal to or less than 25µm;
b) 08-50mg of povidone;
c) 15-85mg of disintegrant in a weight ratio of sodium starch glycolate to crospovidone is about 0.6:1 to 1:0.6;
d) 0.5-3.50mg of colloidal silicon dioxide;
e) 1.8-12mg of magnesium stearate;
Wherein compositions contains less than 0.15% of the individual impurity and not more than 1.5% of total impurities by weight relative to eslicarbazepine when measured by HPLC after storage for 6 months at 40oC/75% relative humidity.

In another aspect, an invention provides the process for producing a pharmaceutical solid dosage form which comprises steps of:
a) mixing eslicarbazepine acetate with excipients selected from sodium starch glycolate, crospovidone, colloidal silicon dioxide;
b) granulating the mixture obtained in step “a” using binder solution comprising povidone;
c) drying the granules obtained in step “b” to get a LOD% in the range of from about 0.5% to about 4% was achieved;
d) optionally milling and then blending the granules with suitable lubricant which is further compressed to get tablet dosage form; wherein, the obtained lubricated blend in step “d” has a bulk density of 0.40 to 0.60 g/ml, tapped density from about 0.50 to 0.80 g/ml and hausner ratio of less than 1.60 and tablet has a water content of 1-5% w/w as measured by Karl Fischer analysis.

Another aspect of an invention provides pharmaceutical composition of the present invention in the manufacture of a medicament for treating epilepsy, partial-onset seizures as a monotherapy or adjunctive therapy.

DETAILED DESCRIPTION OF THE INVENTION

The term “composition”, as in solid pharmaceutical composition, is intended to encompass a drug product comprising Eslicarbazepine or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, and other inert ingredient(s) (pharmaceutically 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, immediate release tablets, caplets, capsules (immediate or modified release) (hard and soft or liquid filled soft gelatin capsules) 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.

The term “excipient”, means a pharmacologically inactive component such as a diluent, binder, disintegrant, glidant, lubricant, coloring agent or the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for veterinary as well as human pharmaceutical use. Reference to an excipient includes both one and more than one such excipient.

The term “Eslicarbazepine” is used in broad sense to include not only "Eslicarbazepine" per se but also its pharmaceutically acceptable salts, solvates, hydrates, enantiomers, derivatives, isomers, polymorphs, prodrugs thereof, and also its various crystalline and amorphous forms. The term "Eslicarbazepine" used in this specification means the S-isomer in substantially pure form, i.e. at least 98% pure. The amount of Eslicarbazepine acetate according to the invention may be present at 80 to 90% by weight based on total weight of the composition.

The particle size of eslicarbazepine acetate having a particle size distribution of D90 equal to or less than 30µm. Preferably D90 equal to 15 to 25 µm, more preferably D90 equal to or less than 22µm and most preferably D90 is 20µm or 19µm or 18µm or 17µm or 16µm or 15µm or in the range of 10-20 µm. The particle size of eslicarbazepine acetate was measured using a Malvern light scattering technique (wet method).

The term "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counter ions including fumarate, maleate, phosphate, L-tartrate, citrate, acetate, oxalate, and sulfate.

The term “bulk density” as used herein according to the present invention is bulk density of a powder or granules and is the ratio of the mass of an untapped powder or granules sample and its volume including the contribution of the interparticulate void volume. Hence, the bulk density depends on both the density of powder or granules and the spatial arrangement of particles in the powder or granular bed. The bulk density is expressed in grams per milliliter (g/ml) although the international unit is kilogram per cubic meter (1g/ml=1000kg/m3) because the measurements are made using cylinders. It may also be expressed in grams per cubic centimeter (g/cm3). The bulk density of a powder is determined by measuring the volume of a known mass of powder sample that may have been passed through a sieve, into a graduated cylinder (Method A). Bulk density and Tapped density can be determined using compendial bulk density apparatus, such as the method given in Test 616 “Bulk Density and Tapped Density,” United States Pharmacopeia 29, United States Pharmacopeial Convention, Inc., Rockville, Md., 2005 (“USP”). The bulk density of lubricated blend according to the present invention is from 0.40 g/ml to 0.60 g/ml, preferably from 0.40 g/ml to 0.55 g/ml, more preferably 0.40 g/ml to 0.50 g/ml and most preferably the bulk density of lubricated blend is 0.45 g/ml to 0.48 g/ml.

The term “Tapped density” as used herein according to the present invention is an increased bulk density attained after mechanically tapping a container containing the powder sample. Tapped density is obtained by mechanically tapping a graduated measuring cylinder or vessel containing a powder sample. The tapped density is expressed in grams per milliliter (g/ml). The tapped density of lubricated blend according to the present invention is from is from 0.50 g/ml to 0.80 g/ml, preferably from 0.55 g/ml to 0.75 g/ml, more preferably 0.60 g/ml to 0.75 g/ml and most preferably the tapped density of lubricated blend is 0.65 g/ml to 0.70 g/ml.

The term “Hausner ratio (HR)” is a number that is correlated to the flowability of a powder or granular material. The Hausner ratio is determined by measurement of the tapped and untapped (or aerated) bulk density. The granules according to the present invention is having a hausner ratio of less than 1.60, preferably less than 1.55 and more preferably less than 1.50.

Hausner ratio is calculated by formula: V0 / Vf.
V0 – Bulk density of the powder
Vf – Tapped density of the powder.

The term “% by weight of the tablet” refers to the percentage by weight of each ingredient in the core tablet, excluding any exterior coatings.

The term “loss on drying” is a widely used test method to determine the water content of a sample, although occasionally it may refer to the loss of any volatile matter from the sample. The step of drying is obtained by heating the granules to a temperature above room temperature and maintaining the elevated temperature, until the LOD of the granules reaches a desired value. The granules are typically characterized by having a solvent loss on drying at 105°C of less than 4% w/w, preferably less than 3.5% w/w, 3% w/w, 2.5% w/w, 2% w/w and 1.5% w/w.

Methods have been described, for example Karl Fischer (KF) or loss on drying (LOD), to determine liquid, e.g., water, content of solids, such as tablets, powders and granules. LOD measures all volatiles in a sample, while KF is typically used to measure all water. Thus, for a sample containing only water, LOD values are usually less than or equal to KF values for a given sample. Granules containing excipients are conveniently tested for water content by Karl Fischer titration using a Metrohm 684 KF Coulometer according to a published procedure (U.S. Pharmacopoeia, vol. 23, 1995, chapter <921>, U.S. Pharmacopeial Convention, Inc., Rockville, Md.) and manufacturer's Coulometer instructions. According to the present invention the water content in the tablet was measured using the Karl Fischer method. The tablet having a water content between 1 – 5% w/w, preferably tablet having a water content less than 4% w/w and more preferably tablet having a water content less than 3.5% w/w, 3% w/w, 2.5% w/w and 2.0% w/w.

The term “impurity” refers to undesired contents present or produced in a pharmaceutical composition.

The dissolution is performed as per conditions mentioned or provided in office of generic drugs dissolution database and as determined by the USP. The dissolution profile of tablets dosage form was measured in 1000ml of acetate buffer, pH 4.5 using a USP II apparatus (Paddle) at a temperature of 37±0.5°C and a rotation speed of 100 revolutions per minute.

The term "treating" or "treatment" refers to obtaining desired pharmacological and/or physiological effect. The effect can be therapeutic, which includes achieving, partially or substantially, one or more of the following results: partially or totally reducing the extent of the disease, disorder or syndrome; ameliorating or improving a clinical symptom or indicator associated with the disorder or delaying, inhibiting or decreasing the likelihood of the progression of the disease, disorder or syndrome.

The term “about” is used herein to mean approximately, roughly, around, or in the regions of. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of 10 percent.

The term “stable” as used herein refers to formulations that substantially retain the label amount of the therapeutically active ingredient during storage for commercially relevant times, and the drug-related impurity contents in the formulations remain within the acceptable limit.

In one embodiment, the invention relates to a solid pharmaceutical composition comprising Eslicarbazepine or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof with one or more pharmaceutically acceptable excipient.

In another embodiment, an invention provides a solid pharmaceutical composition comprising:
a) 80-90% w/w of Eslicarbazepine or its pharmaceutically acceptable salt thereof, wherein particles of eslicarbazepine or a salt thereof have a D90 equal to or less than 30µm;
b) 2-8% w/w of povidone;
c) 5-20% w/w of disintegrant selected from sodium starch glycolate, crospovidone or a combination thereof;
d) 0.1-1% w/w of colloidal silicon dioxide;
e) 0.8-2.0% w/w of magnesium stearate;
Wherein at least 80% of eslicarbazepine dissolves within 45 minutes in a 1000ml of pH 4.5 acetate buffer at a temperature of 37±0.5°C using a USP apparatus-2 at a paddle rotation of about 100 rpm.

In another embodiment, an invention provides a solid pharmaceutical composition comprising:
a) 80-90% w/w of Eslicarbazepine or its pharmaceutically acceptable salt thereof, wherein particles of eslicarbazepine or a salt thereof have a D90 equal to or less than 30µm;
b) 2-8% w/w of povidone;
c) 5-20% w/w of disintegrant selected from sodium starch glycolate, crospovidone or a combination thereof;
Wherein the weight ratio of eslicarbazepine or its pharmaceutically acceptable salt thereof to povidone is 1:0.04 to 1:0.06.

In another embodiment, an invention provides a solid pharmaceutical composition comprising:
a) 80-90% w/w of Eslicarbazepine or its pharmaceutically acceptable salt thereof, wherein particles of eslicarbazepine or a salt thereof have a D90 equal to or less than 25µm;
b) 2-8% w/w of povidone;
c) 5-20% w/w of disintegrant in a weight ratio of sodium starch glycolate to crospovidone is about 0.6:1 to 1:0.6;
Wherein compositions contains less than 0.15% of the individual impurity and not more than 0.5% of total impurities by weight relative to eslicarbazepine when measured by HPLC after storage for 6 months at 40oC/75% relative humidity.

In another embodiment, an invention provides a solid pharmaceutical composition comprising:
a) 200-800mg of Eslicarbazepine or its pharmaceutically acceptable salt thereof, wherein particles of eslicarbazepine or a salt thereof have a D90 equal to or less than 30µm;
b) 08-50mg of povidone;
c) 15-85mg of disintegrant selected from sodium starch glycolate, crospovidone or a combination thereof;
d) 0.1-1% w/w of colloidal silicon dioxide;
e) 0.8-2.0% w/w of magnesium stearate;
Wherein compositions contains less than 0.15% of the individual impurity and not more than 0.5% of total impurities by weight relative to eslicarbazepine when measured by HPLC after storage for 6 months at 40oC/75% relative humidity.

In another embodiment, an invention provides a solid pharmaceutical composition comprising:
a) 200-800mg of Eslicarbazepine or its pharmaceutically acceptable salt thereof, wherein particles of eslicarbazepine or a salt thereof have a D90 equal to or less than 30µm;
b) 08-50mg of povidone;
c) 15-85mg of disintegrant selected from sodium starch glycolate, crospovidone or a combination thereof;
Wherein the weight ratio of eslicarbazepine or its pharmaceutically acceptable salt thereof to povidone is 1:0.04 to 1:0.06.

In another embodiment, an invention provides a solid pharmaceutical composition comprising:
a) 200-800mg of Eslicarbazepine or its pharmaceutically acceptable salt thereof, wherein particles of eslicarbazepine or a salt thereof have a D90 equal to or less than 30µm;
b) 08-50mg of povidone;
c) 15-85mg of disintegrant in a weight ratio of sodium starch glycolate to crospovidone is about 0.6:1 to 1:0.6;
Wherein at least 80% of eslicarbazepine dissolves within 45 minutes in a 1000ml of pH 4.5 acetate buffer at a temperature of 37±0.5°C using a USP apparatus-2 at a paddle rotation of about 100 rpm.

In another embodiment, an invention provides a solid pharmaceutical composition comprising:
a) 80-90% w/w of Eslicarbazepine or its pharmaceutically acceptable salt thereof, wherein particles of eslicarbazepine or a salt thereof have a D90 equal to or less than 25µm;
b) 2-8% w/w of povidone;
c) 5-20% w/w of disintegrant selected from sodium starch glycolate, crospovidone or a combination thereof;
d) 0.1-1% w/w of colloidal silicon dioxide;
e) 0.8-2.0% w/w of magnesium stearate;
Wherein at least 80% of eslicarbazepine dissolves within 45 minutes in a 1000ml of pH 4.5 acetate buffer at a temperature of 37±0.5°C using a USP apparatus-2 at a paddle rotation of about 100 rpm.

In another embodiment, an invention provides a solid pharmaceutical composition comprising:
a) 80-90% w/w of Eslicarbazepine or its pharmaceutically acceptable salt thereof, wherein particles of eslicarbazepine or a salt thereof have a D90 equal to or less than 30µm;
b) 2-8% w/w of povidone;
c) 5-20% w/w of disintegrant in a weight ratio of sodium starch glycolate to crospovidone is about 0.6:1 to 1:0.6;
d) 0.1-1% w/w of colloidal silicon dioxide;
e) 0.8-2.0% w/w of magnesium stearate;
Wherein at least 80% of eslicarbazepine dissolves within 45 minutes in a 1000ml of pH 4.5 acetate buffer at a temperature of 37±0.5°C using a USP apparatus-2 at a paddle rotation of about 100 rpm.

In another embodiment, an invention provides a solid pharmaceutical composition comprising:
a) 80-90% w/w of Eslicarbazepine or its pharmaceutically acceptable salt thereof, wherein particles of eslicarbazepine or a salt thereof have a D90 equal to or less than 20µm;
b) 2-8% w/w of povidone;
c) 5-20% w/w of disintegrant selected from sodium starch glycolate, crospovidone or a combination thereof;
d) 0.1-1% w/w of colloidal silicon dioxide;
e) 0.8-2.0% w/w of magnesium stearate;
Wherein compositions contains less than 0.15% of the individual impurity and not more than 0.5% of total impurities by weight relative to eslicarbazepine when measured by HPLC after storage for 6 months at 40oC/75% relative humidity.

In another embodiment, an invention provides a solid pharmaceutical composition comprising:
a) 200-800mg of Eslicarbazepine or its pharmaceutically acceptable salt thereof, wherein particles of eslicarbazepine or a salt thereof have a D90 equal to or less than 30µm;
b) 08-50mg of povidone;
c) 15-85mg of disintegrant selected from sodium starch glycolate, crospovidone or a combination thereof;
d) 0.5-3.50mg of colloidal silicon dioxide;
e) 1.8-12mg of magnesium stearate;
Wherein weight ratio of eslicarbazepine or its pharmaceutically acceptable salt thereof to povidone is 1:0.04 to 1:0.06 and at least 80% of eslicarbazepine dissolves within 45 minutes in a 1000ml of pH 4.5 acetate buffer at a temperature of 37±0.5°C using a USP apparatus-2 at a paddle rotation of about 100 rpm.

In another embodiment, an invention provides a solid pharmaceutical composition comprising:
a) 200-800mg of Eslicarbazepine or its pharmaceutically acceptable salt thereof, wherein particles of eslicarbazepine or a salt thereof have a D90 equal to or less than 30µm;
b) 08-50mg of povidone;
c) 15-85mg of disintegrant in a weight ratio of sodium starch glycolate to crospovidone is about 0.6:1 to 1:0.6;
d) 0.5-3.50mg of colloidal silicon dioxide;
e) 1.8-12mg of magnesium stearate;
Wherein at least 80% of eslicarbazepine dissolves within 45 minutes in a 1000ml of pH 4.5 acetate buffer at a temperature of 37±0.5°C using a USP apparatus-2 at a paddle rotation of about 100 rpm.

In another embodiment, an invention provides a solid pharmaceutical composition comprising:
a) 200-800mg of Eslicarbazepine or its pharmaceutically acceptable salt thereof, wherein particles of eslicarbazepine or a salt thereof have a D90 equal to or less than 30µm;
b) 08-50mg of povidone;
c) 15-85mg of disintegrant in a weight ratio of sodium starch glycolate to crospovidone is about 0.6:1 to 1:0.6;
d) 0.5-3.50mg of colloidal silicon dioxide;
e) 1.8-12mg of magnesium stearate;
Wherein compositions contains less than 0.15% of the individual impurity and not more than 0.5% of total impurities by weight relative to eslicarbazepine when measured by HPLC after storage for 6 months at 40oC/75% relative humidity.

In another embodiment, an invention provides the process for producing a pharmaceutical solid dosage form which comprises steps of:
a) mixing eslicarbazepine acetate with excipients selected from sodium starch glycolate, crospovidone, colloidal silicon dioxide;
b) granulating the mixture obtained in step “a” using binder solution comprising povidone;
c) drying the granules obtained in step “b” until the desired LOD was achieved;
d) optionally milling and then blending the granules with suitable lubricant which is further compressed to get tablet. Wherein, the obtained lubricated blend in step “d” has a bulk density of 0.40 to 0.60 g/ml, tapped density from about 0.50 to 0.80 g/ml and hausner ratio of less than 1.60.

In another embodiment, an invention provides the process for producing a pharmaceutical solid dosage form which comprises steps of:
a) mixing eslicarbazepine acetate with excipients selected from sodium starch glycolate, crospovidone, colloidal silicon dioxide;
b) granulating the mixture obtained in step “a” using binder solution comprising povidone;
c) drying the granules obtained in step “b” to get a LOD% in the range of from about 0.5% to about 4% was achieved;
d) optionally milling and then blending the granules with suitable lubricant which is further compressed to get tablet dosage form; wherein, the obtained lubricated blend in step “d” has a bulk density of 0.40 to 0.60 g/ml, tapped density from about 0.50 to 0.80 g/ml and hausner ratio of less than 1.60 and tablet has a water content of 1-5% w/w as measured by Karl Fischer analysis.

In another embodiment of the present invention there is provided a pharmaceutical composition comprising Eslicarbazepine or its pharmaceutically acceptable salts, wherein the composition comprises at least one or more pharmaceutically acceptable excipient like diluent, binder, disintegrant, glidant, lubricant and coloring agent.

The term "diluent" or "filler" as used herein is defined as an inert agent designed to increase the weight and/or the size of the pharmaceutical composition, for example in the case of a tablet. Examples of diluents include, but are not limited to microcrystalline cellulose, sodium alginate, silicified MCC, microfine cellulose, mannitol and mixtures thereof. Preferred diluent according to the present invention is microcrystalline cellulose. The diluents according to present invention may be present in an amount from about 0% to about 95% by weight with respect to total weight of the pharmaceutical composition.

The term "binder" as used herein is defined as an agent able to bind particles which cannot be bound only by a compression force. The binder may be present in the form of a single compound or in the form of a mixture of compounds. Examples of binders include, but are not limited to hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose sodium, povidone and mixtures thereof. Preferably the binder is povidone. The binder according to present invention may be present in an amount from 1 to 15%. Preferably, the amount of binder is from 2% to 8% w/w, more preferably, the amount of binder is 4% or 5% or 6%w/w.

The weight ratio of eslicarbazepine acetate to povidone is 1:0.04 to 1:0.06, preferably the weight ratio of eslicarbazepine acetate to povidone is 1:0.045 to 1:0.06, more preferably the weight ratio of eslicarbazepine acetate to povidone is 1:0.05 to 1:0.06 or 1:0.05 or 1:0.052 or 1:0.054 or 1: 0.055.

The term "disintegrant" as used herein is defined as an accelerating agent of the disintegration of the tablet and the dispersion of the active ingredient in water or gastrointestinal fluids. Examples of disintegrants include, but are not limited to croscarmellose sodium, carboxymethyl cellulose calcium, crospovidone, polacrilin potassium, sodium starch glycolate and/or combinations thereof. Preferred disintegrants according to the present invention are selected from sodium starch glycolate, crospovidone or a combination thereof. The disintegrant according to present invention may be present in an amount from about 5 to 20% w/w, preferably, the amount of disintegrant is from about 6% to 15% w/w, more preferably the amount of disintegrant is from about 7% or 8% or 9% or 10%.

The combination of disintegrants are used which are selected from sodium starch glycolate and crospovidone, the weight ratio of sodium starch glycolate to crospovidone is about 0.6:1 to 1:0.6. Preferably, the weight ratio of sodium starch glycolate to crospovidone is about 0.8:1 to 1:0.8 and more preferably, the weight ratio of sodium starch glycolate to crospovidone is about 1:1 or 1:0.9 or 0.9:1.

The term "lubricant" as used herein is defined as an agent able to decrease adhesion of a powder to punches and friction between particles. The lubricant may be present in the pharmaceutical composition in the form of a single compound or in the form of a mixture of compounds. Examples of lubricants include, but are not limited to stearic acid, Zinc stearate, sodium stearyl Fumarate, magnesium stearate. Preferably the lubricant is magnesium stearate. The lubricant is present in an amount from 0.1% to 5% w/w, preferably, the amount of Lubricant is from about 0.5% to 3% w/w, more preferably, the amount of Lubricant is from about 0.8% to 2% w/w, most preferably amount of disintegrant is from about 0.9% or 1% or 1.1% or 1.2%.

The term "glidant" as used herein is defined as an agent improving the fluidity of the powder and thus the filling of the compression chamber of the tablet press. The gliding agent may be present in the pharmaceutical composition in the form of a single compound or in the form of a mixture of compounds. Examples of glidants include, but are not limited calcium silicate, magnesium silicate, magnesium trisilicate, talc and colloidal silicon dioxide or mixtures thereof. Preferred glidant according to the present invention is anhydrous colloidal silica. The glidant preferably, is present in an amount from 0.1 to 5%. Preferably, the amount of glidant is from 0.1% to 3% w/w, more preferably, the amount of glidant is from 0.1 to 1% w/w, most preferably the amount of glidant is present in an amount of about 0.2% or 0.3% or 0.4% or 0.5%.

Surprisingly, it has been found that the pharmaceutical composition of the present invention has been found to have improved stability and dissolution profile coupled with simple manufacturing process at industrial scale and it is bioequivalence to commercially available counterpart tablets APTIOM®.

The following examples serve to illustrate the embodiments of the present invention. However, they do not intend to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.

Examples: The following examples further illustrate the invention and do not limit the scope of the invention.

Example 1: Eslicarbazepine tablets were prepared by using quantitative formula as given in Table 1:

Table – 1:
No Ingredients Quantity per unit
Intra-granular (mg) (% w/w)
1 Eslicarbazepine acetate 800.00 600.00 400.00 200.00 80 - 90
2 Colloidal silicon dioxide 2.52 2.31 1.40 0.63 0.1 - 1
3 Sodium starch glycolate 64.08 58.74 35.60 16.02 3 - 10
Binder
4 Povidone 42.03 38.53 23.35 10.51 2 - 8
5 Purified water Qs Qs Qs Qs -
Extra-granular
6 Magnesium stearate 8.37 7.68 4.65 2.10 0.8 - 2
Tablet weight 917.00 707.26 465.00 229.26 100.00
Q.s: Quantity sufficient

Manufacturing process:
1. Sifting: Sift Eslicarbazepine acetate, Colloidal silicon dioxide and Sodium starch glycolate through #20 mesh and load into RMG.
2. Binder Preparation: Add Povidone into purified water under stirring.
3. Granulation: Granulate the material of step 1 with binder solution (Step 2).
4. Drying: Dry the above granules until the desired LOD was achieved.
5. Milling: Mill step no 4 dried granules in suitable screen.
6. Lubrication: Lubricate the material of step 5 with Magnesium Stearate.
7. Compression: Compress the above blend with suitable punches.
8. Packing: pack the compressed tablets by using HDPE bottles and blisters.

Example 2-3: Eslicarbazepine tablets were prepared by using quantitative formula as given in Table 2-3 respectively:

Table – 2:
No Ingredients Quantity per unit
Intra-granular (mg) (% w/w)
1 Eslicarbazepine acetate 800.00 600.00 400.00 200.00 80 - 90
2 Colloidal silicon dioxide 3.08 1.89 1.40 0.77 0.1 - 1
3 Sodium starch glycolate 40.92 25.11 18.60 10.23 3 - 10
4 Crospovidone 40.92 25.11 18.60 10.23 3 - 10
Binder
5 Povidone 47.85 29.36 21.75 11.96 2 - 8
6 Purified water Qs Qs Qs Qs -
Extra-granular
7 Magnesium stearate 10.23 6.28 4.65 2.56 0.8 - 2
Tablet weight 943.00 687.75 465.00 235.75 100.00
Q.s: Quantity sufficient

Manufacturing process:
1. Sifting: Sift Eslicarbazepine acetate, Sodium starch glycolate, Crospovidone and Colloidal silicon dioxide through #20 mesh and load into RMG.
2. Binder Preparation: Add Povidone into purified water under stirring.
3. Granulation: Granulate the material of step 1 with binder solution (Step 2).
4. Drying: Dry the above granules until the desired LOD was achieved.
5. Milling: Mill step no 4 dried granules in suitable screen.
6. Lubrication: Lubricate the material of step 5 with Magnesium Stearate.
7. Compression: Compress the above blend with suitable punches.
8. Packing: pack the compressed tablets by using HDPE bottles and blisters.

Table-3
No Ingredients Quantity per unit
Intra-granular (mg) Actual (% w/w) Claimed (% w/w)
1 Eslicarbazepine acetate 800.00 600.00 400.00 200.00 86.02 80 - 90
2 Colloidal silicon dioxide 2.8 2.1 1.4 0.7 0.30 0.1 - 1
3 Sodium starch glycolate 37.2 27.9 18.6 9.3 4 3 - 10
4 Crospovidone 37.2 27.9 18.6 9.3 4 3 - 10
Total disintegrant 74.4 55.8 37.2 18.6 8 5 - 20
Binder
5 Povidone 43.5 32.625 21.75 10.875 4.68 2 - 8
6 Purified water Qs. Qs. Qs. Qs. - -
Extra-granular
7 Magnesium stearate 9.3 6.975 4.65 2.325 1 0.8-2
Tablet weight 930.00 697.50 465.00 232.50 - -

Manufacturing process: same as per table-2

Eslicarbazepine granules prepared as per Example 1 and 2-3 has the following properties which is represented in Table 4:

Table – 4: Properties of obtained granules:
Elements Results
Bulk Density 0.48 g/ml
Tapped Density 0.685 g/ml
Hausner Ratio 1.43
Water content Less than 3.5 %w/w
Loss on drying (105°C) Less than 3.0 %w/w

Dissolution study: The dissolution profile of the tablets (800; 600; 400 and 200mg) prepared using quantitative composition as mentioned in example 1 and 2-3 is shown in Table 4 below:

Table 5: Dissolution profile of commercially marketed tablets (APITIOM®) and Examples 1, 2-3 at particular time intervals:

Time point (Minutes) % drug released ± 5%
APITIOM® Example 1 Example 2-3
5 30 38 43
10 56 60 60
15 73 69 69
20 79 74 74
30 85 81 80
45 88 87 85

Two dissolution profiles (APITIOM® and Example 1, 2-3) are considered similar based on f1 and f2 results of above table.

Stability studies:

Tablet dosage form prepared in Example 1 and 2-3 was subjected to Accelerated stability testing as per the ICH guidelines at temperature 40°±2°C and relative humidity of 75%±5% for 6 months. The tablet dosage form was placed in a high density polyethylene (HDPE) bottles exposed to above mentioned condition and then evaluated for impurity profile which is shown in Table 5:

Table 5: Results of stability tests by high performance liquid chromatography method:

Impurities / Related compounds Examples 1 and 2-3
1 Month 3 Months 6 Months
Oxcarbazepine Not detected Not detected Not detected
Carbamazepine Not detected Not detected Not detected
Oxcarbazepine Enol acetate 0.05 0.05 0.05
10-Methoxy Carbamazepine Not detected Not detected Not detected
Eslicarbazepine Propionate 0.06 0.06 0.06
Any individual known impurity NMT 0.15% NMT 0.15% NMT 0.15%
Total impurities NMT 1.5% NMT 1.5% NMT 1.5%
NMT – Not more than

The present formulation clearly indicates excellent chemical stability upon storage at accerlerated stability conditions at 40°±2°C and 75%±5% relative humidity for six months showed no evidence of any degradation products and no reduction in the content of active substance.
,CLAIMS:WE CLAIM:

1. A solid pharmaceutical composition comprising:
a) 80-90% w/w of Eslicarbazepine or its pharmaceutically acceptable salt thereof, wherein particles of eslicarbazepine or a salt thereof have a D90 equal to or less than 30µm;
b) 2-8% w/w of povidone;
c) 5-20% w/w of disintegrant in a weight ratio of sodium starch glycolate to crospovidone is about 0.6:1 to 1:0.6;
d) 0.1-1% w/w of colloidal silicon dioxide;
e) 0.8-2.0% w/w of magnesium stearate;
Wherein at least 80% of eslicarbazepine dissolves within 45 minutes in a 1000ml of pH 4.5 acetate buffer at a temperature of 37±0.5°C using a USP apparatus-2 at a paddle rotation of about 100 rpm.

2. A solid pharmaceutical composition comprising:
a) 200-800mg of Eslicarbazepine or its pharmaceutically acceptable salt thereof, wherein particles of eslicarbazepine or a salt thereof have a D90 equal to or less than 30µm;
b) 08-50mg of povidone;
c) 15-85mg of disintegrant in a weight ratio of sodium starch glycolate to crospovidone is about 0.6:1 to 1:0.6;
d) 0.5-3.50mg of colloidal silicon dioxide;
e) 1.8-12mg of magnesium stearate;
Wherein compositions contains less than 0.15% of the individual impurity and not more than 0.5% of total impurities by weight relative to eslicarbazepine when measured by HPLC after storage for 6 months at 40oC/75% relative humidity.

3. A solid pharmaceutical composition comprising:
a) 80-90% w/w of Eslicarbazepine or its pharmaceutically acceptable salt thereof, wherein particles of eslicarbazepine or a salt thereof have a D90 equal to or less than 30µm;
b) 2-8% w/w of povidone;
c) 5-20% w/w of disintegrant in a weight ratio of sodium starch glycolate to crospovidone is about 0.6:1 to 1:0.6;
d) 0.1-1% w/w of colloidal silicon dioxide;
e) 0.8-2.0% w/w of magnesium stearate;
Wherein the composition has a bulk density of 0.45 to 0.55 g/ml, tapped density from about 0.50 to 0.65 g/ml.

4. The solid pharmaceutical composition according to claim 1-3, wherein the particles of eslicarbazepine or a salt thereof have a D90 equal in the range of 10-20µm.

5. The solid pharmaceutical composition according to claim 1-3, wherein the eslicarbazepine is in crystalline form.

6. The solid pharmaceutical composition according to claim 2-3, wherein the weight ratio of sodium starch glycolate to crospovidone is 0.8:1 to 1:0.8.

7. The solid pharmaceutical composition according to claim 1-3, wherein the weight ratio of eslicarbazepine acetate to povidone is 1:0.04 to 1:0.06.

8. The solid pharmaceutical composition according to claim 1-3, wherein the water content is 1-5% w/w as measured by Karl Fischer method.

9. The solid pharmaceutical composition according to claim 1-3, wherein the loss on drying (LOD) at 105°C is no more than 4% w/w.

10. The solid pharmaceutical composition according to claim 1-3, wherein the solid pharmaceutical composition is a tablet or capsule, if the solid pharmaceutical composition is a tablet then it is optionally coated.