FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
Provisional Specification [See Sections 10 and rule 13]
TITLE: CONTROLLED RELEASE FORMULATION COMPRISING ANTI-EPILEPTIC DRUGS
Applicant: (a) Astron Research Limited
(b) Nationality: Indian
(c) 10th Floor, Premier House Bodakdev, Opp. Gurudwara Sarkhej - Gandhinagar Highway
(d) Ahmedabad 380054

The following specification describes the invention:

Field of Invention
The present invention relates to a pharmaceutical capsule formulation of antiepileptic drug preferably oxcarbazepine comprising multiple tablets or pellets wherein the individual tablets or pellets are either immediate release or controlled release in nature.
This formulation can be used once a day or twice a day, preferably once a day.
This formulation reduces fluctuation in blood level caused by repeated dose of immediate release drug. The invention further describes the method of preparation of the said pharmaceutical preparation.
Background of the invention
The epileptic seizures are mainly of two types: partial seizures and generalized seizures. Partial seizures can again be of three type; i.e. simple partial, complex partial and partial with secondarily generalized tonic clonic seizure. Generalized seizures are classified as absence seizure, myoclonic seizure and tonic-clonic seizure.
Based on their mechanism of action, anti-epileptic drugs can be classified as sodium channel blockers, calcium current inhibitors, gamma-aminobutyric acid (GABA) enhancers, glutamate blockers, carbonic anhydrase inhibitors etc.
Oxcarbazepine is a keto analog of carbamazepine and is an important antiepileptic drug which acts by sodium channel blocker mechanism. Chemically it is known as 10, 1 l-dihydro-10-oxocarbamazepine. Oxcarbazepine is converted to 10-monohydroxy derivative which is its active metabolite and responsible for the pharmacological effect. Oxcarbazepine is
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considered for monotherapy or adjunct therapy for partial seizures. It is also considered for first line therapy in the treatment of epileptic seizures in many countries.
Oxcarbazepine has poor water solubility. This causes a problem in its dosage form preparation. So to prepare a dosage form having controlled release profile leading to enhanced bioavailabilty of oxcarbazepine is an approach of this invention. In addition to insoluble or difficult to soluble oxcarbazepine is also difficult to achieve a high loading dose of oxcarbazepine in multi tablets or pellets when formulated as sustained release dosage forms. The term high loading as used in this application shall mean at least twenty percent (20%) by weight of total dose of oxcarbazepine.
Repeated dosing of immediate release drug causes fluctuation in the blood level. So preparing a formulation which can preferably be administered once a day and reduce the drawback of repeated dosing is also an approach in this invention.
A pharmaceutical dosage form which can impart both immediate drug effect and sustained drug effect to a patient suffering from epileptic seizures and which can be suitable for once a day use to provide patient compliance is a further approach of this invention.
Prior Art
W09835681 discloses a film coated oxcarbazepine formulation wherein the median particle size of the active ingredient is approximately 2 to 12 urn, preferably 4 to 12um.
US5472714 reveals a double layered oxcarbazepine tablet containing an inner hydrophilic permeable layer containing white pigment and an outer
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hydrophilic permeable layer containing white pigment in combination with iron (II) oxide pigment.
WO2002094774 describes a composition for oral administration comprising oxcarbazepine and a wetting agent.
WO2004026314 describes once a day oral dosage form consisting of a tablet core and a coating wherein the dosage form produces a constant monohydroxy derivative of oxcarbazepine plasma level for 24 hours for the treatment of epilepsy.
US20040142033 describes a pharmaceutical composition containing oxcarbazepine with sustained release of the active ingredient.
Thus, somehow abridged the problems associated with oxcarbazepine formulation, but there still remains a pressing need for improvement in the existing formulations and to prepare a dosage form which can crack all the adversities related with the active ingredient oxcarbazepine and which can be well-suited to an epileptic patient for once a day use.
Object of the invention
The instant object of the invention is to provide a pharmaceutical dosage
formulation
for epileptic patients which is controlled release in nature to give a sustained
drug effect.
Another object of the invention is to provide a pharmaceutical preparation which can be used once a day or twice a day, preferably once a day by a patient suffering from epileptic seizure.
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The next object of the invention is to prepare a pharmaceutical formulation of antiepileptic drug which reduces the fluctuation of blood level caused by repeated dosing of immediate release tablet.
Another object of the invention is to provide a pharmaceutical preparation preferably capsule comprising of multi-tablets or pellets which individually releases the active ingredient in immediate and in sustained duration of time providing an overall sustained drug action.
Further one more object of the invention is to prepare a pharmaceutical formulation comprising antiepileptic drug preferably carbamazepine derivative, more preferably oxcarbazepine.
Still one more object of the invention is to provide a process of preparation of orally administrable sustained release oxcarbazepine formulation.
Summary of the invention
The present invention provides a pharmaceutical composition(s) and/or dosage form(s) for oral administration suitable for once a day or twice a day preferably once a day to a patient suffering from epileptic seizure, said composition comprising multi tablets or pellets in capsule wherein the individual tablets or pellets are of immediate release or controlled release nature. This formulation reduces fluctuation in blood level caused by repeated dosing of immediate release tablets.
Detail Description of the Invention
The pharmaceutical formulation of the present invention comprises multi-tablets or pellets in a capsule. The tablets or pellets filled inside the capsule are of immediate release and controlled release nature.
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The terms controlled release, sustained release, sustained action, prolonged action, extended action; extended release, timed release, pulsatile release etc. should be considered to be within the scope of the present invention.
The immediate release tablets or pellets containing of the active ingredient provides an instant drug effect which is then maintained for prolonged time duration by the remaining controlled release tablets or pellets and hence the formulation of the present invention provides an overall sustained drug action.
The preferred pharmaceutical formulation of the present invention comprises core tablets or pellets in a capsule wherein one or more tablets or few of the pellets are immediate release and rest of the tablets or pellets are controlled release in nature.
The part of the formulation providing immediate release in which the core tablet or pellets may be coated or uncoated whereas the rest providing the controlled release are coated by rate controlling polymers which controls the release of the drug in response to the pH environment at a given site in the distal region of the g.i. tract.
The weight of each individual tablet in the formulation of present invention is 5- 50 % of the total weight of formulation and in case of pellets each pellet can be from 0.1 to 5 % of total weight of the formulation.
The immediate release tablet(s) or pellet(s) of the present invention comprise of 10 - 90 % of the active pharmaceutical ingredient, 1 - 15 % of the binder, 1-15% of the disintegrant, 0.25 - 10 % of the lubricant and a solvent system as per the requierment.
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The sustained release tablet or tablets of the present invention comprise of 10-90 % of the active ingredient, 1-15% of the binder, 1-15% of the disintegrant, 0.25-8% of the lubricant and solvent system as per the requierment.
The immediate release pellets comprises of 10 - 90 % of the active ingredient and 1 - 15 % of other excipients. The sustained release pellets comprise of 10 - 90 % of the active ingredient, 1 - 15 % of other excipients and 5 - 25 % of the coating composition.
In case of coated tablets or pellets, the coating polymer is selected from water soluble or insoluble film coating or release controlling polymer.
The rate controlling polymeric coating comprises of 2- 50 % of polymer, 0.1 -20 % of plasticizer, 0.2 - 15 % of acid neutralize^ 0.01 - 15 % of emulsifier, 0.05 - 15 % of antisettling agents and 0.02 - 15 % of pigments. The active pharmaceutical ingredient is selected from anti-epileptic drugs preferably carbamazepine or its derivative, more preferably oxcarbazepine or pharmaceutically acceptable salt thereof.
The average particle size (dl0%) of the active pharmaceutical ingredient used is in the formulation of the present invention ranges from 2 to 50 microns and d90% is in the ranges from 10 to 200 microns.
The preferred binder for the present invention may be selected from the group comprising of but not limited to starch, methyl cellulose, polyvinylpyrollidone, ethyl cellulose, polyethylene glycol, polyvinyl alcohol, carboxymethyl cellulose, hydroxypropyl cellulose and the like.
The preferred lubricant used in the invention may be selected from the group comprising of but not limited to magnesium stearate, other alkali earth metal
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stearate like calcium, zinc etc., colloidal anhydrous silica, talc, sodium steary1 fumarate, glycery1 monostearate and the like.
The preferred disintegrant used in the formulation of present invention can be selected from the group comprising of but not limited to cross-linked polymers such as crospovidone; starches or modified starches such as sodium starch glycolate, clays such as bentonite or veegum; celluloses or cellulose derivatives; crosslinked cellulose such as croscarmellose sodium, resins such as polacrillin potassium and the like.
The preferred polymers for film coating are selected from the group comprising of but not limited to zein, hydroxypropylmethylcellulose, hydroxyethyl cellulode, methyl cellulose, hydroxypropylcellulose, polyvinylpyrollidone, polyvinyl alcohol and the like.
The preferred coating polymers used for the controlling the release of the drug from the tablets or pellets is selected from the group comprising of but not limited to methacrylic acid copolymers preferablymethacrylic acid copolymer type-A, methacrylic acid copolymer type-B, methacrylic acid copolymer type-C, polyvinyl acetate phthalate, hydroxylpropylmethylcellulose phthalate, cellulose acetate phthalate and the like.
The sustained release tablets or pellets may have a combination of a hydrophilic film coating & a rate controlling polymeric coating or a rate controlling polymer coating only. The sustained release tablets within a single capsule may have the same or different rate controlling polymer coatings. The same rate controlling polymers may be used for coating of multiple units in different proportions.
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Acid neutralizer is selected from the group comprising of but not limited to magnesium oxide, sodium hydroxide, potassium hydroxide, ammonia solution, ammonium chloride and the like.
Plasticizer is selected from the group comprising of but not limited to polyethylene glycol, propylene glycol, diethyl phthalate, triethyl citrate, acetylated triethyl citrate, methyl citrate, triacetin and the like.
The anti settling agents used in the preparation of rate controlling polymer coating solution is selected from the group comprising of but not limited to talc, anhydrous silica and the like.
The pigments used for polymer coating are selected from the group comprising but not limited to iron oxide, titanium dioxide, phthalocyanine blue and the like.
Emulsifier is selected from the group comprising of but not limited to Tween-80, lecithin, a polysorbate, polyoxyethylene hardened castor oil, macrogol and the like.
The capsule used to enclose the tablets is selected from but not limited to hard gelatin capsule, soft gelatin capsule, HPMC capsules and the like.
Process for preparation of the dosage form
The dosage form of the present invention is prepared by preparing tablets of immediate release or sustained release nature and filling them in a capsule.
Preparation of immediate release tablet(s): The API is blended with binder preparation, dried and then lubricated. Then it is compressed to form tablets.
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Preparation ofsustained release tablet(s): The tablets are coated by rate controlling polymers to control the release of the drug in response to the pH environment at a given site in the distal region of the g.i. tract.
The method of preparation used for these tablets or pellets is wet granulation type. The API is blended with binder preparation, dried and lubricated. The granules are compressed to form tablets. In case of pellets, wet mass of drug & binder solution can be extruded, spheronised and dried to obtain dried pellets. The immediate release tablets or pellets are coated with the film coating polymer or kept uncoated and the sustained release tablets or pellets may be seal or sub coated and/or directly coated with rate controlling polymer. The polymer coating solution used for obtaining sustained release may be the same or different in nature.
Throughout this specification it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
Example
The present invention has been described by way of example only, and it is to be recognized that modifications thereto falling within the scope and spirit of this specification, and which would be obvious to a person skilled in the art based upon the disclosure herein, are also considered to be included within the scope of this invention.
The formulation of the present invention is a hard gelatin capsule containing multiple tablets or pellets of oxcarbazepine.
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The amount of active pharmaceutical ingredient i.e. oxcarbazepine in the formulation of the present invention is 150 - 900 mg preferably 600 mg.
The present invention can be illustrated by but not limited to following example(s).
Table-l. Composition for core tablet

Sr. No, Ingredients Range J
Dry Mi xing
1 Oxcarbazepine 10-90% |
Granulation
2 PVP K 30 1-15%
3 Water ~
Extra granular Ingredients
4 Crospovidone 1-15%
Lubrication
5 Colloidal Anhydrous Silica 0.25-10%
6 Magnesium Stearate 0.25-10%
Procedure: Weighed quantity of the active ingredient is granulated with a suitable binder, sieved and lubricated using suitable lubricants. The prepared blend is tabletted using a rotary compression machine. These tablets will be coated either by film coating solution or rate controlling solution. The composition of film coating solution is given in table 2 and the composition of rate controlling solution used can be from table 3 or 4.
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Table-2. Composition for Film coating;

Sr.No. Ingredients Range
1 HPMC E5 1-20%
2 Light Magnesium Oxide 0.2-15%
3 PEG 4000 0.1-15%
4 Water Q.S.
Table-3. Composition for rate controlling polymer coating:

Sr.No. Ingredients Range
1 Eudragit L30 D55 5-50%
2 Sodium Hydroxide pellets 0.2-10%
3 Diethyl Phthalate 0.1-10%
4 Tween-80 0.01-15%
5 Ferric Oxide Red 0.02-10%
6 Colloidal Anhydrous Silica 0.01-15%
7 Water Q.S... .
Table-4 Composition for Rate controlling polymer coating:

Sr. No. Ingredients Range
1 Eudragit SI00 2-30%
2 Ammonia Solution(l N) 0.5-15%
3 Triethyl Citrate 0.1-20%
4 Ferric Oxide Yellow 0.02-15%
5 Titanium Dioxide 0.01-15%
6 Talc 0.05-15%)
7 Water Q.S.
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A combination of immediate and sustained release tablets were placed in a capsule.
Dissolution of of sustained release capsule The dissolution profile of the formulation of the present invention is as below:
Table-5

Sr.No. Time (Hours) Dissolution Medium Limits
1 3 0.1NHC1 5 % 50%
2 6 Trisodium buffer pH 5.5 25%-70%
3 9 Trisodium buffer pH 6.8 40%-90%
4 12 Trisodium buffer pH 6.8 50%-95%
5 18 Trisodium buffer pH 6.8 NLT 70%
Example 2
In this example, different parts of the prepared pellets are filled in a capsule. Table 6 Composition for core pellets:

Sr.No Ingredient Qty (%)
Granulation
1. Oxcarbazepine 10-75
2. HPMC E5 1-20%
3. MCC 1-15%
4. Water ~
Lubrication
5. Magnesium Stearate 1-4%
Process '
Weigh and mix defined quantities of the sieved active ingredient & MCC. Granulate the blend using a solution of HPMC in water and pass the wet mass through a extruder. The extruded mass is processed in a spheronizer to obtain pellets. Dry the pellets.
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The film coating solution and rate controlling polymer solution is used as of table 3 and 4.
The percentage weight gain of the above said coating could be varied from 5 -25 % to be used in the same capsule. The pellets of the above said coating may contain same or different weight of the rate controlling polymer.
The pellets prepared by the below methods were filled into capsule, the weight of the immediate release and different rate controlling polymer coated pellets could be present in the different proportion.
Dissolution of Sustained release capsule containing pellets:
The dissolution profile of the formulation of the present invention is as below:
Table 7

Sr.No. Time (Hours) Dissolution Medium Limits
1 3 0.1 NHC1 5 %-50%
2 6 Trisodium buffer pH 5.5 25%-70%
3 9 Trisodium buffer pH 6.8 40%-90%
4 12 Trisodium buffer pH 6.8 50%-95%
5 18 Trisodium buffer pH 6.8 NLT 70%
Dated this 24tn April 2006.

Ketana Laljib'hai Babaria
Registered Patent Agent
For and on behalf of the Applicant
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