Claims:1. A liquidpharmaceutical composition suitable for oral administration comprising ofZonisamide and one or more pharmaceutically acceptable excipients.
2. A liquid pharmaceutical composition according to claim 1, wherein one or more pharmaceutically acceptable excipients are selected from the group comprising of one or more suspending agents, one or more thickening agents, one or more preservatives, one or more buffering agents, one or more sweetening agents, one or more flavoring agents and one or more vehicles or combination thereof.
3. A liquid pharmaceutical composition according to claim 2, wherein one or more suspending agent is selected from the group comprising of sodium alginate, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, CMC, Na-CMC, microcrystalline cellulose, tragacanth, xanthan gum, bentonite, carrageen, guar gum and colloidal silicon dioxide.
4. A liquid pharmaceutical composition according to claim 2, wherein one or more preservative is selected from the group comprising of benzyl alcohol, chloro-butanol, chloro-cresol, alkyl esters of paraben, phenol, phenyl ethanol, propylene glycol, chloroform, benzoic acid, potassium sorbate, sodium benzoate.
5. A liquid pharmaceutical composition according to claim 2, wherein one or more buffering agent is selected from the group comprising of sodium acetate, sodium citrate, ammonium sulfate, sodium phosphate, disodium hydrogen phosphate, potassium citrate, citric acid monohydrate and trisodium citrate dihydrate.
6. A liquid pharmaceutical composition according to claim 2, wherein one or more sweetening agent is selected from the group comprising of sucralose, sucrose, glycerol, liquid glucose, sorbitol, maltitol, saccharin sodium and aspartame.
 

7. A liquid pharmaceutical composition according to claim2, wherein one or more flavoring agent is selected from the group comprisingof essential oils and fruit flavors, wherein essential oil is selected from the group comprising of peppermint oil, orange oil, and lemon oil and fruit flavour comprising peppermint flavour, raspberry flavour, strawberry flavour and tutti-fruit flavour.
8. A liquid pharmaceutical composition according to claim 2, wherein one or more vehicle is selected from the group comprising of aqueous vehicles and oily vehicles, wherein aqueous vehicles are selected from the group comprising purified water, hydro-alcoholic, polyhydric alcohols and buffers and oily vehicle is selected from the group comprising vegetable oils, mineral oils, organic oily bases or emulsified bases.
9. A liquid pharmaceutical composition comprising Zonisamide and one or more pharmaceutically acceptable excipients selected from the group comprising of suspending agents consisting of Microcrystalline Cellulose &Carboxymethylcellulose Sodium Dispersion and Xanthan gum, buffering agents consisting of citric acid monohydrate and tri sodium citrate dihydrate, preservatives consisting of sodium benzoate, sweetening agents consisting of sucralose, flavouring agents consisting of strawberry flavor and vehicles consisting of purified water, wherein the liquid composition has pH between 3.5 and 5.0 and the pharmaceutical composition has a particle size distribution of Zonisamide of D10-13.0µm, D50-53.0µm and D90-131.0µm.
10. A process for the preparation of a pharmaceutical composition of Zonisamideaccording to any one claim of 1 to 9, comprising of following steps:
(i) Forming a solution by dissolving buffering agent, preservative and sweetening agent in water under stirring;
(ii) Dispersing suspending agent and Zonisamide in the solution obtained in step (i) under stirring;
(iii) Dispersing flavoring agent in solution obtained in step (ii) under stirring;
(iv) Homogenizing the solution obtained in step (iii) with homogenizer;and
(v) Making up final volume by purified water by mixing properly under stirring.
, Description:FIELD OF THE INVENTION
The present invention relates, in general, to the pharmaceutical field, and more precisely it relates to a pharmaceutical composition for the oral administration of Zonisamideand to the process for the preparation thereof. In particular, the present invention relates to the oral liquid composition comprising Zonisamide.

BACKGROUND OF THE INVENTION
Zonisamide, chemically known as 1,2-benzoxazol-3-ylmethanesulfonamide having an empirical formula C8H8N2O3Sand a molecular weight of 212.2 gm/mol has a following structural formula:

Zonisamide is a benzisoxazole derivative, originally synthesized in Japan in 1974 during exploratory research on psychiatric drugs, where it was subsequently identified as having anticonvulsant activity during screening. Zonisamide is thought to act through its blocking of voltage-dependent sodium channels, reduction of voltage-dependent T-type inward calcium currents, binding to the gamma-aminobutyric acid (GABA)–benzodiazepine receptor complex, and facilitation of both dopaminergic and serotonergic neurotransmission. Zonisamide was approved in Japan in 1989 as both monotherapy and adjunctive therapy for children and adults with generalized or partial seizures. Zonisamide was approved in 2000 in the USA as adjunctive therapy in the treatment of partial seizures in adults with epilepsy. For epilepsy, most studies have used oral zonisamide in daily doses ranging from 200 to 600 mg/day, divided in 2 daily doses, adjusted to maintain serum levels of15 to 40 µg/ml.Zonisamide is also proposed for treatment of other diseaselike tardive dyskinesia.It is to be sold, when combined with bupropion, under the brand name empatic for obesity.Zonisamide has been studied for and used as a migraine preventative medication, and has also been shown to be effective in some cases of neuropathic pain.It has also been used off-label by psychiatrists as a mood stabilizer to treat bipolar depression.
EP2301537 describe a composition comprising zonisamide or a pharmaceutically acceptable salt thereof for use in reducing the weight of an obese subject.

EP2285374 describe a composition comprising a combination ofat least two compounds chosen from the group consisting ofzonisamide, dyphylline, tadalafil, argatroban, acamprosate, cinacalcet, terbinafine, cilostazol, baclofen, phenformin, amlodipine and sulfisoxazole, or salts or prodrugs or derivatives or sustained release formulations thereof, for simultaneous, separate or sequential administration.

EP2222296 and EP2164487 describe a pharmaceutical composition comprising an AMPA receptor antagonist, Zonisamide and one or more pharmaceutically acceptable carriers.EP1683516 describes a stable pharmaceutical dosage form comprising, in intimate mixture, solid particulate zonisamide and at least one pharmaceutically acceptable excipient.

EP1913935 describes a process for preparing a stable zonisamide pharmaceutical composition, comprising subjecting zonisamide to wet granulation with a granulation liquid to form a granulated mixture as the stable zonisamide pharmaceutical composition wherein the granulation liquid is selected from purified water, alcohol and mixtures thereof.

EP1656094 describes a method of improving the safety of patients receiving zonisamide treatment for epileptic seizures comprising providing a patient with a therapeutically effective amount of zonisamide, and informing the patient that during the course of zonisamide therapy, if (s)he experiences one or more symptoms chosen from the group of abdominal pain, hypovolemia, shock, nausea, anorexia, vomiting, and abdominal distention, to seek immediate medical attention.

EP1503755 describes a method of reducing weight in an overweight subject, said method comprising administering to an overweight subject a pharmaceutical composition comprising zonisamide, in an amount effective to reduce weight in said subject, wherein said weight loss is significant and sustained.
EP1682522 describes a process for the manufacturing of zonisamide compound.

EP1505967 describes use of a first compound and a second compound in the preparation of a medicament for treating obesity in a mammal in need of such treatment, wherein said first compound is bupropion, and said second compound is at least one weight-loss promoting anticonvulsant.

EP1040830 describes a medicament for neurodegenerative diseases comprising zonisamide or an alkali metal salt thereof as an active ingredient.

EP1954241 describes a sustained-release pharmaceutical formulation comprising, zonisamide; and a retardant excipients, wherein the pharmaceutical formulation has a sustained-release dissolution profile comprising at least one dissolution characteristic selected from: (a) Less than 70% of the zonisamide in the sustained-release pharmaceutical formulation is dissolved within a first hour in a standard dissolution test, and (b) Less than 75% of the zonisamide in the sustained-release pharmaceutical formulation is dissolved within a second hour in a standard dissolution test , wherein said pharmaceutical formulation comprises at least 5% by weight of said retardant excipients.EP1411931 describes a method of treating headache in a subject in need of such treatment, said method comprising, administering to a subject a pharmaceutical composition comprising zonisamide, in an amount effective to relieve headache.

Currently Zonisamideis available in oral solid dosage forms like capsule and tablet. Some patient particularly children and the seriously ill persons are not able to swallow solid dosage form.Liquid dosage forms are used fairly commonly by young children or the elders who have trouble swallowing the solid oral dosage forms. Its action is more rapid than solid dosage forms. Therefore there is a need to develop oral liquid dosage form for Zonisamide.

OBJECT OF THE INVENTION
The principal object of the present invention is to provide an oral liquid pharmaceutical composition forZonisamide.
A further object of the present invention is to provide a process for the preparation of the oral liquid pharmaceutical composition of Zonisamideof the present invention.

A further object of the present invention is to provide composition of Zonisamidefor use in adjunctive therapy in the treatment of partial seizures in adults with epilepsy.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides a liquid pharmaceutical composition comprising Zonisamideand one or more pharmaceutically acceptable excipients selected from the group comprising of suspending agent, thickening agent, preservatives, buffering agents, sweetening agents, flavoring agents, vehicles or combinations thereof with improved stability and palatability.

There is also provided a method of preparing the liquid pharmaceutical composition comprising Zonisamideand one or more pharmaceutically acceptable excipients selected from the group comprising suspending agent, thickening agent, preservatives, buffering agents, sweetening agents, flavoring agents, vehicles or combinations thereof.

DETAILED DESCRIPTION OF THE INVENTION
Zonisamide, chemically known as 1,2-benzoxazol-3-ylmethanesulfonamide having an empirical formula C8H8N2O3Sand a molecular weight of 212.2 gm/mol has a following structural formula:

Zonisamide is a benzisoxazole derivative, originally synthesized in Japan in 1974 during exploratory research on psychiatric drugs, where it was subsequently identified as having anticonvulsant activity during screening. Zonisamide is thought to act through its blocking of voltage-dependent sodium channels, reduction of voltage-dependent T-type inward calcium currents, binding to the gamma-aminobutyric acid (GABA)–benzodiazepine receptor complex, and facilitation of both dopaminergic and serotonergic neurotransmission. Zonisamide was approved in Japan in 1989 as both monotherapy and adjunctive therapy for children and adults with generalized or partial seizures. Zonisamide was approved in 2000 in the USA as adjunctive therapy in the treatment of partial seizures in adults with epilepsy. For epilepsy, most studies have used oral Zonisamidein daily doses ranging from 200 to 600 mg/day, divided in 2 daily doses, adjusted to maintain serum levels of 15 to 40 µg/ml. Zonisamide is also proposed for treatment of other disease like tardive dyskinesia. It is to be sold, when combined with bupropion, under the brand name empatic for obesity. Zonisamide has been studied for and used as a migraine preventative medication, and has also been shown to be effective in some cases of neuropathic pain. It has also been used off-label by psychiatrists as a mood stabilizer to treat bipolar depression.

Currently Zonisamideis available in oral solid dosage forms like capsule and tablet. Some patient particularly children and the seriously ill persons are not able to swallow solid dosage form. Liquid dosage forms are used fairly commonly by young children or the elders who have trouble swallowing the solid oral dosage forms. Its action is more rapid than solid dosage forms. Therefore there is a need to develop oral liquid dosage form for Zonisamide.

Therefore, in one of the embodiments, the present invention provides a pharmaceutical composition comprising Zonisamideand one or more pharmaceutically acceptable excipients.

In one of the further embodiments, the pharmaceutical composition comprises Zonisamideand one or more pharmaceutically acceptable excipients selected from the group comprising of suspending agent, thickening agent, preservatives, buffering agents, sweetening agents, flavouring agents, vehicles or combinations thereof.

In one of the further embodiments, the pharmaceutical composition comprises Zonisamideand one or more suspending agent, one or more thickening agent, one or more preservatives, one or more buffering agents, one or more sweetening agents, one or more flavouring agents and one or more vehicles or combination thereof.

In one of the preferred embodiments, the pharmaceutical composition comprisesZonisamide, a suspending agent, a thickening agent, a preservative, a buffering agent, a sweetening agent, a flavouring agent, a vehicle or combination thereof.

In one of the preferred embodiments, the pharmaceutical composition is a liquid pharmaceutical composition.

In one of the preferred embodiments, the liquid pharmaceutical composition is suitable for oral administration.

In one of the further embodiments, the pharmaceutical composition is useful for the manufacture of a medicament.

In one of the further embodiments, the pharmaceutical composition is useful as a medicament.

In one of the further embodiments, the pharmaceutical composition is useful for the manufacture of a medicament in the treatment of partial seizures in adults with epilepsy.

Suspending agents referred in the present invention are the compounds which are added to increase the viscosity of the solution, which is necessary to prevent sedimentation of the suspended particles. Suspending agents also act as thickening agents therefore sometimes they are also referred as thickening agents as well. Examples of suitable suspending agent are but not limited to sodium alginate, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, CMC, Na-CMC, microcrystalline cellulose, tragacanth, xanthan gum, bentonite, carageenan, guar gum, colloidal silicon dioxide. The preferred suspending agent is MCC & Na-CMC Dispersion (Avicel® RC591) and xanthan gum.

Buffering agents referred in the present invention are the compounds which provide stability and pH control to the pharmaceutical formulations. Examples of suitable buffering agents are but not limited to sodium acetate, sodium citrate, ammonium sulfate, sodium phosphate, disodium hydrogen phosphate, potassium citrate, citric acid monohydrate, trisodium citrate dihydrate. The preferred buffering agents are citric acid monohydrate and trisodium citrate dihydrate.

Preservatives referred in the present invention are the compounds which are included in pharmaceutical dosage form to prevent the growth of microorganisms during the product’s manufacture and shelf life. Examples of the suitable preservatives are but not limited to benzyl alcohol, chloro-butanol, chloro-cresol, alkyl esters of paraben, phenol, phenyl ethanol, benzoic acid, potassium sorbate, sodium benzoate etc. and antimicrobial solvents likepropylene glycol, chloroform etc.The preferredpreservative is sodium benzoate.

Sweetening agentsreferred in the present invention are the compounds that impart sweetness and improve patient compliance through taste masking. Examples of the suitable sweetening agents are but not limited to sucralose, sucrose, liquid glucose, glycerol, sorbitol, maltitol, saccharin sodium and aspartame.The preferredsweetening agent is sucralose.

Flavouring agents referred in the present invention are the compounds which are added to increase patient acceptance of the drug by masking the specific taste sensations. Examples of suitable flavouring agent are but not limited to essential oilsincluding peppermint oil, orange oil, and lemon oil etc. or can be selected from fruit flavour, e.g. peppermint flavour, strawberry flavour, tutti fruit flavour etc. The preferred flavouring agent is strawberry flavour.

Vehicles referred in the present invention are the liquid bases which carry drug and other excipients in dissolved or dispersed state and can be selected from either aqueous vehicles or oily vehicles. Examples of suitable aqueous vehicles are but not limited to purified water, hydro-alcoholic, polyhydric alcohols and buffers, while suitable examples of oily vehicles are but not limited to vegetable oils, mineral oils, organic oily bases or emulsified bases. The preferred aqueous vehicle is purified water.

In one of the further embodiments, the present invention provides process for the preparation of the pharmaceutical composition comprising Zonisamideand one or more pharmaceutically acceptable excipients selected from the group comprising of suspending agent, thickening agent, preservatives, buffering agents, sweetening agents, flavouring agents, vehicles or combinations thereof.

In one of the preferred embodiments, the present invention provides process for the preparation of the pharmaceutical composition comprising Zonisamideby dissolving the preservative, buffering agent and sweetening agent in one part of water while adding the suspending agent, flavouring agent and Zonisamideactive ingredient in other part of water, and making up thefinal volume to required quantity.

In one of the preferred embodiments, the pharmaceutical composition has a pH in between 3.5 and 5.0.In one of the further preferred embodiments, the pharmaceutical composition has a particle size distribution of Zonisamideof D10-13.0µm, D50-53.0µm and D90-131.0µm.

BEST MODE OF CARRYING OUT THE INVENTION
EXAMPLES
The pharmaceutical composition of the present invention is explained in more detail with reference to the following examples. These examples are provided by way of illustration only and should not be construed as limit to the scope of the claims in any manner.

Example-1: A liquid oral pharmaceutical composition comprising Zonisamide
Table-1: Zonisamide liquid composition
Ingredients mg/ml
Zonisamide 20.00
Avicel RC591 (Microcrystalline Cellulose &Carboxymethylcellulose Sodium Dispersion) 20.00
Sodium benzoate 2.00
Xanthan gum 3.50
Citric acid monohydrate pH 4-5
Tri-sodium citrate dihydrate pH 4-5
Sucralose 2.00
Strawberry flavour 0.10
Purified water Q.S to 1.0 ml

Method of Preparation: The process for the preparation of the liquid composition of Zonisamideinvolves dissolving required quantities ofsodium benzoate, citric acid monohydrate, tri-sodium citrate and sucralose in purified water, followed by dispersingrequired quantities of Avicel®RC 591(Microcrystalline Cellulose &Carboxymethylcellulose Sodium Dispersion), xanthan gum,Zonisamide and Strawberry flavour separately in purified water, mixing both the mixtures, homogenizing it and making up the final volume to the required quantity of batch size with purified water.

Those who are skilled in the art can understand that variations in the above described process for the preparation of liquid compositions of the present invention can be adopted which are well within the skills of the skilled artisan. One can change sequences of the steps in the above mentioned process for the purposes of suitability and convenience without affecting the quality and characteristics of the resulting product.

Those who are reasonably skilled in the art can easily understand that similar liquid formulations using Zonisamide with other suitable excipients, mentioned in the foregoing paragraphs may be prepared in the above mentioned formula using above mentioned processes for the preparation. Such other examples of compositions and processes of preparation thereof are also within the ambit of the invention disclosed and claimed in the present application.
Example 2: Stability studies of the pharmaceutical composition prepared in Example 1
The oral liquid pharmaceutical composition prepared according to Example 1 exhibits unexpected stability profile when tested after one (1), three (3) and six (6) months under the conditions 40°C/25% RH and 25°C/40% RH. The liquid composition according to the present invention possess very less amount of impurities and highest degree of purity. The results of the stability tests conducted are summarized in the table below.

Table-2: Stability study results of Zonisamide liquid composition of Example-1
Parameters Results
Initial 40°C/25% RH 25°C/40% RH
1 month 3 months 6 months 3 months 6 months
Description White to Off white suspension Complies Complies Complies Complies Complies
pH 4.32 4.18 4.30 4.27 4.30 4.26
Assay of Zonisamide (%) 97.2 102.3 101.3 102.7 101.2 103.0
Impurity A ND ND ND ND ND ND
Unknown Impurities (%) 0.06 0.06 0.06 0.05 0.06 0.06
Total Impurities (%) 0.07 0.08 0.09 0.05 0.10 0.06
ND = Not Detected

It should be understood that various changes and modifications to the presently preferred embodiments, examples and processes described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present subject matter and without diminishing its intended advantages. It is therefore intended that such changes and modifications be covered by the appended claims.