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Solid Dispersion Of Eslicarbazepine

Abstract: The present invention relates to solid dispersion pharmaceutical. compositions comprising Eslicarbazepine or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof. The present invention also relates to a process for preparing such solid oral pharmaceutical composition comprising Eslicarbazepine acetate and at least one pharmaceutically acceptable excipient and/or carrier. The prior art highlights challenges of Eslicarbazepine during formulation development with convention granulation techniques. Compositions ofEslicarbazepine acetate prepared as per present invention, exhibited desirable formulation technical attributes.

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Patent Information

Application #
Filing Date
07 January 2016
Publication Number
03/2018
Publication Type
INA
Invention Field
CHEMICAL
Status
Email
Parent Application

Applicants

JUBILANT GENERICS LIMITED
PLOT 1A. SECTOR 16A, NOIDA-201 301, UP,INDIA

Inventors

1. NITHIYANANDAM, RAVIKUMAR
CF-04 GKS RESIDENCY, 55-A GOVINDASWAMY LAYOUT, ASHOK NAGAR, CHETTY STREET, COIMBATORE-641 001, TAMIL NADU, INDIA
2. GAT, GANESH VINAYAK
6115 UNITED WESTERN CHS, GODAVARI, KARVENAGAR, PUNE 411052, MAHARASHTRA, INDIA
3. NAKHAT, PREMCHAND DALICHANDJI
GURUKRUPA MEDICALS AND ELECTRONIC LOHI(BAZAR),TQ, DARWHA, DIST. YAVATMAL-445 210, MAHARASHTRA, INDIA
4. JAIN, VIVEK
HOUSE NO. 278 SECTOR -5, CHIRANJIV VIHAR, GHAZIABAD 201001, UTTAR PRADESH, INDIA
5. SHARMA, PRIYANK
30, NEB, SHRI RAMNAGAR, MAIN TEMPO ROAD, ALWAR 301001, RAJASTHAN, INDIA
6. KUMAR, DINESH
1073/1, SECTOR-39B, CHANDIGARH-160036, INDIA

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: o 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 r contains inactive ingredients like povidone, croscarmellose sodium, and magnesium 2 ooo o o CM o -CsL 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. 0) 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 £ o range of about 20 to about 50 \LXX\ for the preparation of controlled release compositions g „ of Eslicarbazepine. c &*•%*'*&• tfr-e. face 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 i n i it 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 18 CD G) co Q. CD 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, o o> ooo CO o CN o CN CO 7 CO o 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.- / / 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 / ' ' • • • ' 20 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: CD o co Q. CD CN E o o> o o o CO o CN o CN 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 * * 6 - - - - - 0.1-20 21 o -CNC CO "p CO o -It,. xerrT—r? 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 i 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. / 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.

Documents

Application Documents

# Name Date
1 201611000599-GPA-(07-01-2016).pdf 2016-01-07
2 201611000599-Form-5-(07-01-2016).pdf 2016-01-07
3 201611000599-Form-3-(07-01-2016).pdf 2016-01-07
4 201611000599-Form-2-(07-01-2016).pdf 2016-01-07
5 201611000599-Form-1-(07-01-2016).pdf 2016-01-07
6 201611000599-Correspondence Others-(07-01-2016).pdf 2016-01-07
7 201611000599-Other Patent Document-060117.pdf 2017-01-09
8 201611000599-Other Patent Document-060117-.pdf 2017-01-09
9 201611000599-Form 5-060117.pdf 2017-01-09
10 201611000599-Form 3-060117.pdf 2017-01-09
11 201611000599-Form 26-060117.pdf 2017-01-09
12 201611000599-Form 2(Title Page)-060117.pdf 2017-01-09