Title of Invention

SUSTAINED RELEASE ANTI-EPILEPTIC COMPOSITIONS

Abstract The invention provides sustained release pharmaceutical composition in the form of single layer / bilayer / multilayer tablets, wherein the composition comprises of a) carbazepine or its derivative such as oxcarbazepine; b) erosion controller; and c) wetting agent.
Full Text FORM-2
THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
(See Section 10 and Rule 13)
"SUSTAINED RELEASE ANTI-EPILEPTIC COMPOSITIONS"
Themis Laboratories Pvt. Ltd. having its administrative office at Unit No. S - 4 , Khira Industrial Estate, B.M Bhargava Road, Santacruz West, Mumbai 400054, Maharashtra, India an Indian Company
The following specification describes the invention.

FIELD OF INVENTION
This invention relates to sustained release monolithic or multilayer tablet compositions comprising Carbazepine (also known as Carbamazepine) or its derivatives such as oxcarbazepine and a process for the preparation of such sustained release tablets.
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BACKGROUND OF INVENTION
Carbazepine and its derivatives such as Oxcarbazepine (10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide) are antiepileptic agents used in monotherapy and adjunctive therapy in the treatment of partial seizures. On oral administration it is
10 completely absorbed and extensively metabolized by reduction, to its pharmacologically active metabolite, the monohydroxy derivate of oxcarbazepine.
Monotherapy and adjunctive therapy of oxcarbazepine is initiated with a dose of 600 mg/day given in 2 divided doses per day. Therapeutic effects are seen at doses between
15 600 mg/day and 2400 mg/day necessitating multiple administrations. Available market formulations are required to be administered more than once in a day. Multiple administrations cause inconvenience to patients. It results in frequent peaks and troughs concentrations of active substances in the blood. This change in concentration of active substance in blood is not desirable for therapy. Administering larger quantities in
20 conventional forms is not desirable as adverse events increase qualitatively and quantitatively with increasing quantities of oxcarbazepine administered. Therefore there is a need to provide a dosage form containing large quantities of oxcarbazepine that is released in controlled manner to get a once a day composition.
25 U.S. Publication 20060141037 described bilayer oxcarbazepine tablets comprising: a) a first or immediate release layer containing a diluent, a binder, a disintegrant, a lubricant and an oxcarbazepine or its salts or its polymorphs intended for immediate delivery b) a second or controlled release layer including an oxcarbazepine for controlled drug delivery, a matrix forming gelling agent, a wetting agent, a binder, hydrophilic solutes, and a
30 lubricant. Matrix forming gelling agent being essential for controlling the release of oxcarbazepine.
U.S. Publication 20060057203 described once a day oral dosage forms consisting of a tablet core and a coating wherein the core comprises oxcarbazepine, optionally a filler and
35 at least one further excipient selected from the group comprising cellulose ethers,
carboxyvinyl polymer of acrylic acid cross linked with alkyl ethers of sucrose, carboxyvinyl polymer of acrylic acid cross linked with alkyl ethers of pentaerythritol and

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polymethacrylates.

US 5284662 teaches an osmotic dosage form to deliver carbamazepine comprising (a) core comprising (i) carbamazepine; (ii) an effective amount of a crystal habit modifier for
5 said carbamazepine selected from the group of specified cellulose derivatives and gelatin; (iii) from about 2% to about 15% of the total core weight of a mixture of at least two different hydroxy-C1-C4 alkyl celluloses, wherein the ratio of the higher viscosity hydroxy-Ci -C4 alkyl cellulose to the lower viscosity hydroxy-Ci-C4 alkyl cellulose is about 2:1; (iv) a C6 sugar alcohol; (v) a mono- or disaccharide; (vi) from zero to an effective amount of a
10 tabletting lubricant; and (vii) from zero to an effective amount of a wetting agent; said C6 sugar alcohol and said mono or disaccharide together comprising from about 15% to about 60% of the core total weight and the weight ratio of the C6 sugar alcohol to said mono- or disaccharide is from about 1:9 to about 9:1; (b) a semi-permeable wall around said core permeable to water or gastric fluid; and (c) a hole through said semipermeable
15 wall connecting said core with the external environment. Besides multiple special chemical requirements and complex processing techniques, use of costly, sophisticated and complicated machinery is necessary to work the invention.
US 6296873 teaches an erodible oral composition for sustained release delivery of
20 carbamazepine or a derivative thereof at a zero-order release kinetics comprising: (a) carbamazepine or the derivative thereof; (b) an erodible polymeric matrix comprising at least one hydrophilic polymer or a mixture of two or more hydrophilic polymers, having viscosity between about 3 and about 100,000 mpa.s (cp) at concentration of 2% at 20. degree. C. and a molecular weight between about 10,000 and about 246,000; wherein
25 said composition erodes and releases carbamazepine or the derivative thereof in a zero-order release kinetics. This invention teaches monolithic tablets of erodible hydrophilic cellulose polymer matrix.
U.S. Patents 5192550 and 6534090 describe osmotic dosage forms.
30
US 5660861 teaches an osmotic dosage form for administering an antiepileptic drug in the
gastrointestinal tract having a pH of 1 to 8 of a patient, comprising 0.5wt% to 90wt% of an
antiepileptic drug, and a pharmaceutically acceptable carrier comprising 10wt% to 75wt%
of a carboxymethylcellulose, and 0.1wt% to 25wt% of a polyvinylpyrrolidone. Presence of
35 carboxymethylcellulose and polyvinylpyrrolidone are essential components of the
composition. This invention has same drawbacks as in case of US 5284662.

3

U.S. Publication 20040185097 describes a solid, controlled release oral pharmaceutical composition comprising: (a) a therapeutically effective amount of a pharmaceutically active ingredient; and (b) a controlled release modifying complex comprising: (i) a primary release modifying agent; (ii) a secondary release modifying agent; and (iii) an auxiliary
5 release modifying agent wherein said primary, secondary and auxiliary release modifying agents are present in amounts that synergistically extend the release of the pharmaceutically active ingredient. Use of multiple release modifying agents in specific synergistic amounts is essential part of invention.
10 U.S publication 20040185095 described a sustained release oxcarbazepine composition and process to prepare a composition wherein mixture relative to its total weight, contains 60 to 95% by weight of oxcarbazepine, 3 to 30% by weight of microcrystalline cellulose, 1 to 20% by weight of ammonium methacrylate copolymer and/or polymethacrylic acid polymer, 0.05 to 4% by weight of disintegrant and dye is prepared and then compacted.
15
U.S. Patents 4327725, 4612008, 4765989 and 4783337 provide dosage forms for controlled release of drug over an extended time. These dosage forms can deliver many drugs. But certain drugs like phenytoin with poor solubility are not readily manufactured and delivered from these dosage forms due to incomplete release. Oxcarbazepine also
20 has poor solubility.
Therefore prior art has disclosed sustained release Oxcarbazepine formulations such as
I. Those comprising matrix forming gelling agent e.g. US20060141037 or in
US20060057203 comprising plurality of ingredients for delaying release, or U.S Patent
25 application publication 20040185095 describing process and composition comprising
compressing processed mixture of oxcarbazepine, MCC, ammonium methacrylate copolymer and/or polymethacrylic acid polymer, disintegrant and dye, or
II. Osmotic delivery systems as in US5192550, US6534090, US5284662 and
US5660861, or US6210712, or
30 III. Those making use of multiple release modifying agents in complicated manner to work the invention as in U.S. publication 20040185097.
Processes described in prior art for production of controlled-release dosage forms cannot be generalized. It is easy to provide sustained release for selected active ingredients
35 having low dose and low water solubility. There are limitations to deliver high dose of low water soluble active ingredient. Some of these limitations or disadvantages are such that systems
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i) dose dumping or releasing more than 60%w/w, or
ii) take comparatively low quantity of active ingredient giving bulkier, expensive and not
so patient friendly dosage form, or
iii) use of costly and complex manufacturing procedures and/or equipments,
5
Therefore there exists an urgent need for a controlled-release delivery dosage form for once a day administration of Oxcarbazepine that would provide immediate release of oxcarbazepine followed by sustained release. There is a need to provide a composition and a process to provide formulation that will be able to carry higher payloads of drugs
10 that have low water solubility and yet would render the drug bioavailable.
OBJECTS OF THE INVENTION:
The main object of the invention is to provide sustained release tablet compositions comprising Carbazepine or its derivative such as oxcarbazepine upto 80%w/w of
15 composition; Erosion controller upto 15%w/w, Wetting agent upto 3%w/w of composition and at least one pharmaceutically acceptable excipient such that not more than (NMT) 60%w/w, NMT 80%w/w and not less than (NLT) 80%w/w of Carbazepine or its derivative such as oxcarbazepine is released in one hour, two hours and four hours respectively.

20 Another object of the invention is to provide a process to prepare sustained release tablet compositions comprising Carbazepine or its derivative such as oxcarbazepine upto 80% w/w of composition, Erosion controller upto 15%w/w of composition, Wetting agent upto 3%w/w of composition and at least one pharmaceutically acceptable excipient such that NMT 60%w/w, NMT 80%w/w and NLT 80%w/w of Carbazepine or its derivative such as
25 oxcarbazepine is released in one hour, two hours and four hours respectively.
Yet another object of the invention is to provide a bilayer sustained release tablet compositions comprising Carbazepine or its derivative such as oxcarbazepine in both layers such that first layer or immediate release layer comprises Carbazepine or its
30 derivative such as oxcarbazepine upto 60%w/w of the total weight of Carbazepine or its derivative such as oxcarbazepine present in the bilayer tablet and second layer or Controlled release layer comprises Carbazepine or its derivative such as oxcarbazepine in an amount upto 70%w/w of the total weight of Carbazepine or its derivative such as oxcarbazepine present in the bilayer tablet; an erosion controller in an amount upto
35 15%w/w of bilayered tablet; wetting agent in an amount upto 3% w/w of bilayered tablet; and at least one pharmaceutically acceptable excipient so as to release NMT 60%w/w, NMT 80% w/w and NLT 80%w/w of Carbazepine or its derivative such as oxcarbazepine
5

in one hour, two hours and four hours respectively.
Yet another object of the invention is provide a process to prepare bilayer sustained release tablet compositions comprising Carbazepine or its derivative such as
5 oxcarbazepine in both layers such that first layer or immediate release layer comprises Carbazepine or its derivative such as oxcarbazepine upto 60%w/w of the total weight of Carbazepine or its derivative such as oxcarbazepine present in the bilayer tablet and second layer or Controlled release layer comprises Carbazepine or its derivative such as oxcarbazepine in an amount upto 70% w/w of the total weight of Carbazepine or its
10 derivative such as oxcarbazepine present in the bilayer tablet; an erosion controller in an amount upto 15%w/w of bilayered tablet; wetting agent in an amount upto 3% w/w of bilayered tablet and at least one pharmaceutically acceptable excipient so as to release NMT 60%w/w, NMT 80%w/w and NLT 80%w/w of Carbazepine or its derivative such as oxcarbazepine in one hour, two hours and four hours respectively.
15
Yet another object of the invention is to provide sustained release tablet compositions comprising Carbazepine or its derivative such as oxcarbazepine; and a process to prepare such compositions so as to provide sufficient blood levels over a desired prolong period.
20 Yet another object of the invention is to provide patient friendly monolithic, bilayered or multilayered tablet or compositions comprising Carbazepine or its derivative such as oxcarbazepine that is able to carry upto 1200mg of Carbazepine or its derivative such as oxcarbazepine without causing burst effect and exhibiting sustained release of active
ingredient for desired period; and a process to prepare such compositions.
25
Yet another object of the invention is to provide a user friendly process to prepare patient friendly sustained release tablet compositions comprising Carbazepine or its derivative such as oxcarbazepine without the use of costly and complex manufacturing procedures and/or sophisticated equipments.
30
Yet another object of the invention is to provide a process to manufacture stable, once-a-day, monolithic, bi-layered or multi-layered compositions comprising Carbazepine or its derivative such as oxcarbazepine.
35
6

SUMMARY OF INVENTION
Accordingly the invention provides sustained release monolithic, bilayered or multilayered tablet compositions comprising Carbazepine or its derivative such as oxcarbazepine upto 80% w/w of composition; Erosion controller upto 15%w/w of composition, Wetting agent
5 upto 3% w/w of composition and at least one pharmaceutically acceptable excipient such that NMT 60%w/w, NMT 80% w/w and NLT 80%w/w of Carbazepine or its derivative such as oxcarbazepine is released in one hour, two hours and four hours respectively.

The invention also provides a process to prepare sustained release monolithic, bilayered
10 or multilayered tablet compositions comprising Carbazepine or its derivative such as oxcarbazepine upto 80% w/w of composition; Erosion controller upto 15%w/w of composition, Wetting agent upto 3% w/w of composition and at least one pharmaceutically acceptable excipient such that NMT 60%w/w, NMT 80% w/w and NLT 80%w/w of Carbazepine or its derivative such as oxcarbazepine is released in one hour, two hours
15 and four hours respectively.
This invention in particular provides bilayered sustained release tablet compositions comprising antiepileptic drug Carbazepine or its derivative such as oxcarbazepine, wherein the drug is present in both the layers such that first layer or immediate release
20 layer comprises Carbazepine or its derivative such as oxcarbazepine upto 60%w/w of the total weight of drug present in the bilayer tablet and second layer or Controlled release layer comprises Carbazepine or its derivative such as oxcarbazepine in an amount upto 70%w/w of the total weight of drug present in the bilayer tablet; an erosion controller in an amount upto 15%w/w of composition; wetting agent in an amount upto 3% w/w of
25 composition; and at least one pharmaceutically acceptable excipient so as to release NMT 60%w/w, NMT 80%w/w and NLT 80%w/w of Carbazepine or its derivative such as oxcarbazepine in one hour, two hours and four hours respectively and a process to prepare such compositions.
30 Further this invention provides sustained release monolithic or multilayer or a bilayer tablet compositions comprising Carbazepine or its derivative such as oxcarbazepine; and a process to prepare such compositions so as to provide sufficient blood levels over a desired prolong period.
35 There is also provided patient friendly sustained release monolithic or multilayer or bilayer tablet compositions comprising Carbazepine or its derivative such as oxcarbazepine that is able to carry upto 1200mg of Carbazepine or its derivative such as oxcarbazepine
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without causing burst effect and exhibiting sustained release of active ingredient for desired period; and a process to prepare such compositions.
This invention also provides a user friendly process to prepare patient friendly sustained
5 release monolithic or multilayer or bilayer tablet compositions comprising Carbazepine or its derivative such as oxcarbazepine without the use of costly and complex manufacturing procedures and/or sophisticated equipments.
This invention also provides a process to manufacture a stable, improved, once-a-day, bi-
10 layered composition comprising Carbazepine or its derivative such as oxcarbazepine.
DESCRIPTION OF THE INVENTION
The present invention achieves the objects by providing a monolithic or multilayer or bilayer tablet composition comprising
15 a) Carbazepine or its derivative such as oxcarbazepine upto 80%w/w of composition;
b) controller is pres`ent upto 15%w/w of composition; and
c) Erosion Wetting agent is present upto 3%w/w of composition.
The present invention in particular achieves the objects by providing a bi-layer
20 composition comprising Carbazepine or its derivative such as oxcarbazepine in both
layers such that first layer or immediate release layer comprises Carbazepine or its
derivative such as oxcarbazepine upto 60%w/w of the total weight of Carbazepine or its
derivative such as oxcarbazepine present in the bilayer tablet and second layer or
Controlled release layer comprises Carbazepine or its derivative such as oxcarbazepine in
25 an amount upto 70% w/w of the total weight of Carbazepine or its derivative such as
oxcarbazepine present in the bilayer tablet; an erosion controller in an amount upto
15%w/w of composition; wetting agent in an amount upto 3% w/w of composition; and at
least one pharmaceutical^ acceptable excipient so as to release NMT 60%w/w, NMT
80%w/w and NLT 80%w/w of Carbazepine or its derivative such as oxcarbazepine in one
30 hour, two hours and four hours respectively and process to prepare such compositions.
The objects of invention are achieved by providing a novel process to prepare monolithic composition comprising steps of
1) Sifting of Carbazepine or its derivative such as oxcarbazepine, and other ingredients
35 such as diluents, disintegrants, wetting agent through suitable sieve;
2) Mixing the sifted material obtained form step 1, in a suitable mixer;
3) Optional preparation of binder solution;
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4) Granulating the blend obtained in step 2, using suitable solvent/binder solution in suitable equipment;
5) Optional drying of granules in suitable dryer to have moisture content of less than 5% w/w; and optionally sifting dried granules through suitable sieve;
5 6) Optionally lubricating the granules; and
7) Compressing the granules into tablets.
In one of the preferred embodiments, the objects are achieved by providing a novel process to prepare multilayer or bilayer tablet composition comprising steps of
10
Preparation of Immediate release granule by:
1) Sifting of Carbazepine or its derivative such as oxcarbazepine, diluents, binder,
disintegrant, colorants through suitable sieve;
2) Mixing the sifted material obtained from step 1, in a suitable mixer;
15 3) Preparation of binder solution if dry binder is not used;
4) Granulating the blend with suitable solvent/binder solution in suitable equipment;
5) Drying suitably the granules at 40-65°C to have LOD less than 5%w/w and optionally sifting dried granules through suitable sieve; and
6) Lubricating suitably the granules with lubricant/s, glidant/s (pre-sifted through suitable
20 sieve);
Preparation of controlled release Granules by:
1) Sifting of Oxcarbazepine, and pharmaceutical excipients such as diluents, disintegrants, erosion controller, wetting agent, binder through suitable sieve;
25 2) Mixing the sifted material obtained in step 1, in suitable mixer;
3) Optional preparation of binder solution;
4) Granulating the blend using suitable solvent / binder solution;
5) Optional drying of granules at 40-65°C in suitable dryer and optionally passing dried
granules through suitable sieve; and;
30 6) Lubricating suitably the granules with lubricant/s, glidant/s (pre-sifted through suitable sieve); and
7) Compressing the granules into layered tablet.
It is surprisingly found that monolithic tablet or bilayered tablet on in-vitro analysis gave
35 release of NMT 60%w/w, NMT 80% w/w and NLT 80%w/w of Carbazepine or its derivative such as oxcarbazepine in one hour, two hours and four hours respectively.
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Invention provides sustained release tablet compositions comprising Carbazepine or its derivative such as oxcarbazepine prepared with conventional equipments like Planetary mixer/Rapid Mixer Granulator /High shear Mixer/ fluidized bed granulator, compression machines including layerpress/Killian/Cadmach layer compression machines, tray dryer /
5 fluidized bed dryer and particle size reducing mills such as Fitzpatrick mill or Cadmill and like machineries such that these tablets are able to take required payloads of active without leading to burst effect, yet giving prolonged release of active ingredient for a desired duration to avoid fluctuations and to achieve desired bioavailability.
10 The tablet compositions prepared as per the present invention comply with the pharmacopoeial requirements assay of Carbazepine or its derivative such as oxcarbazepine, friability, dissolution, total impurities and stability during shelf-life period.
Detailed description of the invention:
15 The invention teaches in particular pharmaceutical compositions in the form of monolithic or multilayer or a bilayer tablet such that tablet releases NMT 60%w/w, NMT 80%w/w and NLT 80%w/w of Carbazepine or its derivative such as oxcarbazepine in one hour, two hours and four hours respectively, comprising a. Carbazepine or its derivative upto 80% w/w of composition;
20 b. Erosion controller upto 15%w/w;
c. Wetting agent upto 3% w/w of composition;
d. at least one pharmaceutically acceptable excipient.
The term "bi-layered tablet or bilayer tablet" mentioned herein relates to a solid dosage
25 form for oral administration, prepared by compressing two different types of granules by tabletting machine used for preparation of layered tablets. Multilayered tablet refers to solid dosage form for oral administration, prepared by compressing more than one type of granules into at least three layered tablet/s by tabletting machine used for preparation of
multilayered tablets.
30
Term oxcarbazepine includes Carbazepine or its derivatives such as oxcarbazepine.
The total amount of oxcarbazepine present in the monolithic or bilayer tablet compositions of the invention varies between 100 mg and 1200 mg, and preferably between 100 mg
35 and 900 mg and more preferably between 150mg and 600mg. In case of monolithic tablet the oxcarbazepine content is upto 80%w/w of composition. In case of bilayered tablets oxcarbazepine upto 70%w/w of the total weight of oxcarbazepine is present in the
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controlled release layer and oxcarbazepine upto 60%w/w, preferable from 25%w/w to 60%w/w of the total weight of oxcarbazepine is present in the immediate release.
It is surprisingly noticed that the compositions of the present invention not only exhibit
5 sustained release of oxcarbazepine but also carry the desired payloads of oxcarbazepine
upto 1200mg.
The diluent or bulking agent is selected from the group consisting of maize starch, lactose, dicalcium phosphate, microcrystalline cellulose, glucose, mannitol, alginates, alkali earth
10 metal salts, clays or polyethylene glycols.
The disintegrating agent used is selected from the group consisting of starches or modified starches such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch, clays such as bentonite; alginates such as sodium alginate or
15 alginic acid; cross-linked poly vinyl pyrrolidone, cross-linked cellulose such as croscarmellose sodium, cross-linked polymers such as crospovidone, ion exchange resin, citric acid, tartaric acid, and sodium bicarbonate.
Lubricants are selected from the group of hydrogenated fatty oils, hydrogenated castor oil,
20 hydrogenated vegetable oils; stearate such as calcium stearate, magnesium stearate, other alkali earth metal stearate; sodium lauryl sulphate, light mineral oil, polyethylene glycol, stearic acid, talc, magnesium lauryl sulphate, sodium oleate, sodium acylate, silica derivatives, vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl monostearate and glyceryl behenate.
25
The controlled release layer includes oxcarbazepine, an erosion controller, a wetting
agent, binder, hydrophilic solutes, a lubricant, a coloring agent, and optionally an antioxidant.
30 The binder is selected from the group consisting of polyvinyl pyrrolidone, cellulose
Derivates such as hydroxypropylmethylcellulose, hydroxypropylcellulose, ethyl cellulose, hydroxyethylcellulose, carboxymethylcellulose and its sodium, potassium and calcium salts; and sugars in powder or liquid form such as mannitol, xylitol, glucose, sucrose, sorbitol, galactose, maltose, lactose, and mixtures thereof and is present in an amount by
35 weight of about 0.5% to about 15%, preferably of about 1% to 14%, more preferably of
about 2% to 13% and most preferably of about 3% to 10% based on the total weight of the
composition.
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Erosion controller is selected from the group of Polyvinylpyrollidone, cellulose polymers
such as methyl cellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxyethylmethylcellulose, carboxymethylcellulose and sodium carboxymethylcellulose.
5
Wetting agents used in the present invention is selected from the group of anionic, cationic or non-ionic agent. Such agents are selected from sodium lauryl sulfate (SLS), propylene glycol, glycerin; poloxyethylene stearates, polyoxyethylene Stearates, Sorbitan esters, sodium laurate, dialkyl sodium sulfosuccinates particularly bis-(2-ethylhexyl)
10 sodium sulfosuccinate, sodium stearate, potassium stearate, sodium oleate, benzalkonium chloride, bis-2-hydroxyethyl oleyl amine, polyoxyethylene sorbitan fatty acid esters, fatty alcohols such as lauryl, cetyl and stearyl alcohols; glyceryl esters such as the naturally occurring mono-, di-, and tri-glycerides; fatty acid esters of fatty alcohols and other alcohols such as propylene glycol, polyethylene glycol, sorbitan, sucrose, and
15 cholesterol. Preferred wetting agent is polysorbate-80 and sodium lauryl sulphate and is present in amount upto 3% w/w of composition, preferably from 0.25% to 2%w/w and more preferably from 0.5% to 1.5%w/w of the composition.
Any colorant approved and certified by the FDA for use in pharmaceuticals can be used in 20 the invention.
The present invention is also related to a process for the preparation of monolithic or
multilayer tablet compositions such as bilayer tablets comprising oxcarbazepine. The wet
granulation process is suitable to work the invention. It comprises following steps
25 1) blending sifted oxcarbazepine with sifted diluents such as mannitol, lactose, starch,
microcrystalline cellulose, glucose, talcum, dextrin or alginate;
2) Granulating with suitable binders such as aqueous binders commonly used for wet
granulation such as polyvinyl pyrrolidone, ethyl cellulose, and sugars in powder or
liquid form as described above.
30 3) Mixing wetting agent with the binder solution gives better spread. Non-aqueous
binders such as ethyl cellulose also give desired granules.
4) Optionally drying, and optionally dried milling/sifting the granulate and optionally
blending with flow regulators, lubricants or mould release agents before it is
compressed in a tabletting machine to monolithic or multilayered tablets such as
35 bilayered tablets.
The process for preparation of bilayered tablets comprises preparation of two types of
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granules followed by compression as described below:
Preparation of Immediate release granule:
5 1) Sifting of Carbazepine or its derivative such as oxcarbazepine, diluents, disintegrants, colorants through 40# or suitable sieve;
2) Mixing in a suitable mixer like planetary mixer for about 15 minutes;
3) Preparation of binder solution if dry binder is not used;
4) Granulating the blend with suitable solvent/binder solution in suitable equipment 10 like Planetary mixer/ RMG/ fluidized bed granulator;

5) Drying of granules at 40-65°C to have LOD less than 5% w/w in tray dryer / fluidized bed dryer; sifting of dried granules through 20 # or suitable sieve; and
6) Mixing the granules with lubricant/s, glidant/s;
15 Preparation of controlled release granules:
1) Sifting of Carbazepine or its derivative such as oxcarbazepine, diluents, disintegrants, erosion controller, wetting agent through 40#, or suitable sieve ;
2) Mixing by suitable means;
20 3) Preparation of binder solution;
4) Granulating the blend using binder solution;
5) Optional drying of granules at 40-65°C in suitable dryer like tray dryer / fluidized bed drier; passing dried granules through 20 # or suitable sieve; and;
6) Mixing the granules with lubricant/s, glidant/s;
25
Granules obtained give tablets of desired profile when compressed in the suitable layer compressing machines such as Cadmach layer-press or Manesty Liverpool layer-press or Killian make layer compression machines.
30 The bilayered tablets of the invention release oxcarbazepine NMT 60%w/w and NMT 80%w/w and NLT 80%w/w in first hour, second hour and in 4 hours respectively.
Other features, advantages and objectives of this invention and its preferred embodiments will become apparent from the detailed description, which follow.
35
Detailed Description of the Invention:
Following are non-limiting illustrations of invention.
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Example 1: Preparation of bilayered tablets:
Step 1: Preparation of immediate release granules for compression:
1) Oxcarbazepine and Colloidal Silicon Dioxide were sifted through mesh 40 and mixed in planetary mixer to get blend I.
5 2) Starch, Lactose and Yellow Oxide of Iron were sifted through mesh 100 and mixed in planetary mixer for 10 minutes to get blend II.
3) PVPK-30, polysorbate-80 were dissolved in water to prepare binder solution.
4) Mixed blend II obtained in step 2 with blend I obtained in step 1 in planetary mixer and granulated with the help of binder solution prepared in step 3). Dried the granules
10 at 60°C in tray dryer to have LOD below 5%w/w and sifted through sieve 20.
5) In planetary mixer starch was blended with sifted granules obtained in step 4).
6) Mixed magnesium stearate and talc as lubricating mix.
7) Lubricated sifted granules with lubricating mix as prepared in step 6).

Sr. No. Ingredients Mg/ tablet Gm/batch
1. Oxcarbazepine 150.0 450
2. Colloidal Silicon Dioxide 15 45
3. Starch 20 60
4. Lactose 18.0 54
5. Yellow Oxide of Iron 2.5 7.5
6. PVPK-30 10.0 30
7. Polysorbate-80 2.5 7.5
8. Magnesium Stearate 2.5 7.5
9. Talcum 2.5 7.5
TOTAL 225.0 675
15
Step 2: Preparation of sustained release granules for compression:
1) Sifted Oxcarbazepine and Colloidal Silicone Dioxide through mesh 40, and mixed
in planetary blender to get blend I.
2) Sifted Starch, Lactose and PVPK-30 through mesh 40 to get blend II.
20 3) Dissolved polysorbate-80 in water to prepare binder solution.
4) Mixed blend II obtained in step 2 with Blend I obtained in step 1 in planetary blender and granulated with the help of Binder solution prepared in step 3). Dried the granules at 60°C in tray dryer to have LOD below 5%w/w.
5) Prepared a lubricating mix of Magnesium stearate and Talc.
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6) Sifted the dried granules through mesh 20 and lubricated with lubricating mixture as prepared in step 5).
Sr. No. Ingredients Mg/tablet Gm/batch
1. Oxcarbazepine 450.0 1350
2. Colloidal Silicon Dioxide 45.0 135
3. Starch 45.0 135
4. Lactose 51.0 135
5. PVPK-30 60.0 198
6. Polysorbate – 80 9.0 27
7. Magnesium Stearate 7.5 22.5
8. Talcum 7.5 22.5
TOTAL 675.0 2025








5 Step 3: Compression into bilayered tablets.
Compressed the granules obtained in Step 1 into bi-layered tablet wherein weights of immediate release layer and sustained release layer were adjusted at 225.0 mg and 675.0 mg respectively for total oxcarbazepine content of 600mg. Another portion of granules were used to compress tablets comprising 300mg and 900mg of Oxcarbazepine.
10
Step 4: Film coating bilayered tablets
Tablets obtained in example 1 were film coated with film coating solution as described
below.

15


No. Ingredients Quantity in % w/w
1) HPMC E05 70.00
2) PEG 6000 7.00
3) Iron oxide Yellow 0.27
4) Iron Oxide Red 0.81
5) Titanium Dioxide 10.5
6) Talc 10.5
Method of preparation of film coating dispersion:
1) Dissolved HPMC E 05 in IPA and water was added to it.
2) Dispersed colour, Titanium Oxide and Talc in water.
15

3) Dissolved PEG 6000 in water to get solution.
4) Added solution obtained in step 3 to solution obtained in step 1).
5) Added the dispersion obtained in step 2 to solution obtained in step 4).
6) Filtered the dispersion obtained in step 5) through mesh 100.
5 7) Used dispersion obtained in step 6 for coating tablets.
8) The coating was continued till the weight gain for different strengths was as follows:
Tablet strength 300mg 600mg 900 mg
Weight gain coating solution From 15mg 25mg 40mg




Release profile of film coated tablets
10 In-vitro method of analysis is USP Type 2, Paddle, 100rpm, 37.5°C, 900 ml of water containing 1.5% SLS. Release profile of film coated tablet as per example 1 is as follows.
15 20

Time (hours) %w/w of drug release
Dose
Specification 300 mg 600 mg 900 mg
1 Not more than 60% 50.20 42.65 46.99
2 Not more than 80% 69.42 62.49 62.88
4 Not Less Than 80% 93.81 91.77 86.87
Example 2: Sustained release monolithic tablet
Preparation of sustained release monolithic tablet
1) Oxcarbazepine and Colloidal Silicon Dioxide were sifted twice through mesh 40, and 25 mixed in planetary mixer to get blend I.
2) Starch, Lactose and PVPK-30 were sifted through mesh 40 to get blend II.
3) Polysorbate-80 was dissolved in water to prepare binder solution.
4) Mixed blend II obtained in step 2 with Blend I obtained in step 1 in planetary blender
and granulated with the help of Binder solution prepared in step 3).
30 5) The granules were dried at 60°C in tray dryer to have LOD less than 5%w/w.
6) Prepared a lubricating mix of Magnesium stearate and Talc.
7) Sifted the dried granules through mesh 20 and lubricated with lubricating mixture as prepared in step 5).
16

8) Granules obtained in step 6 were compressed into tablets containing 450mg of oxcarbazepine.

No. Ingredients Mg/ tablet Gm/batch
1. Oxcarbazepine 450.0 1350
2. Colloidal Silicon Dioxide 45.0 135
3. Starch 45.0 135
4. Lactose 45.0 135
5. PVPK-30 66.0 198
6. Polysorbate - 80 9.0 27
7. Magnesium Stearate 7.5 22.5
8. Talcum 7.5 22.5
TOTAL 675.0 2025
5
Release profile of sustained release monolithic tablet
In-vitro method of analysis is USP Type 2, Paddle, 100rpm, 37.5°C, 900 ml of water containing 1.5% SLS. Release profile of monolithic tablet as per example 2 is as follows.



10 15


Time (hours) Cumulative %w/w drug release
1 44.99
2 67.16
4 90.42

17
ABSTRACT
This invention discloses sustained release compositions in the form of monolithic, bilayered or multilayered tablets comprising Carbazepine or its derivatives such as
5 oxcarbazepine and a process to prepare these sustained release compositions such that not more than (NMT) 60%w/w, NMT 80% w/w and not less than 80% w/w of Carbazepine or its derivative such as oxcarbazepine is released in one hour, two hours and four hours respectively. The present invention achieves the objects by providing a composition comprising a) Carbazepine or its derivative such as oxcarbazepine upto 80% w/w of
10 composition; b) erosion controller upto 15%w/w of composition, and c) wetting agent upto 3% w/w of composition.

Documents:

1511-mum-2006-abstract(19-9-2007).pdf

1511-mum-2006-abstract(granted)-(26-3-2011).pdf

1511-mum-2006-abstract.doc

1511-mum-2006-abstract.pdf

1511-mum-2006-cancelled pages(29-11-2010).pdf

1511-mum-2006-claims(19-9-2007).pdf

1511-MUM-2006-CLAIMS(AMENDED)-(29-11-2010).pdf

1511-MUM-2006-CLAIMS(AMENDED)-(29-7-2010).pdf

1511-mum-2006-claims(granted)-(26-3-2011).pdf

1511-MUM-2006-CORRESPONDENCE(17-11-2009).pdf

1511-mum-2006-correspondence(19-9-2007).pdf

1511-MUM-2006-CORRESPONDENCE(20-9-2006).pdf

1511-MUM-2006-CORRESPONDENCE(26-5-2009).pdf

1511-MUM-2006-CORRESPONDENCE(29-7-2010).pdf

1511-mum-2006-correspondence(ipo)-(26-3-2011).pdf

1511-mum-2006-correspondence-received.pdf

1511-mum-2006-description (provisional).pdf

1511-mum-2006-description(complete)-(19-9-2007).pdf

1511-mum-2006-description(granted)-(26-3-2011).pdf

1511-MUM-2006-FORM 1(17-11-2009).pdf

1511-mum-2006-form 1(19-9-2007).pdf

1511-MUM-2006-FORM 1(21-9-2006).pdf

1511-MUM-2006-FORM 1(29-7-2010).pdf

1511-mum-2006-form 13(17-11-2009).pdf

1511-mum-2006-form 18(19-9-2007).pdf

1511-mum-2006-form 2(19-9-2007).pdf

1511-mum-2006-form 2(granted)-(26-3-2011).pdf

1511-mum-2006-form 2(title page)-(19-9-2007).pdf

1511-mum-2006-form 2(title page)-(granted)-(26-3-2011).pdf

1511-mum-2006-form 3(19-9-2007).pdf

1511-mum-2006-form 5(19-9-2007).pdf

1511-mum-2006-form 6(1-5-2009).pdf

1511-mum-2006-form 6(26-5-2009).pdf

1511-mum-2006-form-1.pdf

1511-mum-2006-form-2.doc

1511-mum-2006-form-2.pdf

1511-mum-2006-form-26.pdf

1511-mum-2006-form-3.pdf

1511-mum-2006-form-5.pdf

1511-MUM-2006-OTHER DOCUMENTS(29-7-2010).pdf

1511-MUM-2006-REPLY TO EXAMINATION REPORT(29-7-2010).pdf

1511-MUM-2006-REPLY TO HEARING(29-11-2010).pdf

1511-MUM-2006-WO INTERNATIONAL PUBLICATION REPORT(21-9-2006).pdf


Patent Number 247054
Indian Patent Application Number 1511/MUM/2006
PG Journal Number 13/2011
Publication Date 01-Apr-2011
Grant Date 26-Mar-2011
Date of Filing 21-Sep-2006
Name of Patentee INVENTIA HEALTHCARE PRIVATE LIMITED
Applicant Address UNIT NO. S - 4, KHIRA INDUSTRIAL ESTATE, B.M BHARGAVA ROAD, SANTACRUZ WEST, MUMBAI 400054,
Inventors:
# Inventor's Name Inventor's Address
1 ANTARKAR AMIT KRISHNA HOUSE NO. C / 4 , RANI LAXMI NAGAR, NAGPUR - 440022,
2 SHAH MAYA JANAK 30,"Saujanya",3rd N.S.Road, Vallabhnagar Society,Vile Parle(West), Mumbai-400056
3 SUNIL BEHARILAL JAISWAL 3-4,Panch Watika, Chitnavis Layout, Byramji Town, Nagpur-440 013,
4 SHAJAHAN ABDUL House No.25/50,Kattaboman Street, Narimedu,District Madurai-625002
PCT International Classification Number A61K31/55; A61K9/24
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA