Claims:1. The pharmaceutical oral liquid composition comprising Imatinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
2. The pharmaceutical oral liquid composition according to claim 1, wherein one or more pharmaceutically acceptable excipients are selected from the group comprising of one or more vehicles, one or more solvents, one or more preservatives, one or more buffering agents, one or more sweetening agents, one or more flavouring agents or combination thereof.
3. The pharmaceutical oral liquid composition according to claim 1 or 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 of purified water, hydro-alcoholic, polyhydric alcohols and buffers and oily vehicle is selected from the group comprising of vegetable oils, mineral oils, organic oily bases or emulsified bases.
4. The pharmaceutical oral liquid compositionaccording to claim 1 or claim 2 wherein one or more solvent is selected from the group comprising of ethanol, polyethylene glycols (PEG), sorbitol, glycerin, propylene glycol and benzyl alcohol.
5. The pharmaceutical oral liquid composition according to claim 1 or 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, chloro-butanol.
6. The pharmaceutical oral liquid composition according to claim 1 or claim 2, wherein one or more buffering agent is selected from the group comprising of sodium acetate, sodium citrate, ammonium sulphate, sodium phosphate, disodium hydrogen phosphate, potassium citrate, citric acid monohydrate, trisodium citrate dihydrate.
7. The pharmaceutical oral liquid composition according to claim 1 or claim 2, wherein one or more sweetening agent is selected from the group comprising of sucralose, sucrose, acesulfame potassium, glycerine, liquid glucose, sorbitol, liquidmaltitol, saccharin sodium and aspartame.
8. The pharmaceutical oral liquid composition according to claim 1 or claim 2, wherein one or more flavouring agent is selected from the group comprising of essential oils and fruit flavours, 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-fruity flavour.
9. The process for the preparation of the pharmaceutical oral liquid composition according to any one of claims 1 to 8, wherein the process comprises steps of:
a) Take required quantity of vehicle,
b) Add required quantity of sweetening agent and mix till get homogenously mixed,
c) Add required quantity of preservative and mix till completely dissolved,
d) Add required quantity of Imatinibmesylate and mix till completely dissolved,
e) Add buffering agent till desired pH is attained,
f) Add required quantity of flavoring agent and mix till completely dissolved, and
g) Make up the final desired volume with vehicle.
10. The process for the preparation of the pharmaceutical oral liquid composition according to any one of claims 1 to 8, wherein the process comprises steps of:
a) Take required quantity of vehicle,
b) Add required quantity of solvent and mix till get homogenously mixed,
c) Add required quantity of sweetening agent and mix till get homogenously mixed,
d) Add required quantity of preservative and mix till completely dissolved,
e) Add required quantity of Imatinibmesylate and mix till completely dissolved,
f) Add buffering agent till desired pH is attained,
g) Add required quantity of flavoring agent and mix till completely dissolved, and
h) Make up the final desired volume with vehicle.
, 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 Imatinib and to the process for the preparation thereof. In particular, the present invention relates to the oral liquid composition comprising Imatinib.

BACKGROUND OF THE INVENTION
Imatinib, chemically known as N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)-4-[(4-methylpiperazin-1-yl)methyl]benzamide having an empirical formula C29H31N7O and a molecular weight of 493.6 gm/mol has a following structural formula:

Imatinib is a small molecule kinase inhibitor used to treat certain types of cancer. It is currently marketed by Novartis as Gleevec (USA) or Glivec (Europe/Australia) as its mesylate salt, Imatinibmesylate (INN). Specifically, it is used for chronic myelogenousleukemia (CML) and acute lymphocytic leukemia (ALL) that is Philadelphia chromosome-positive (Ph+) and certain types of gastrointestinal stromal tumors (GIST), systemic mastocytosis, and myelodysplastic syndrome. It is the first member of a new class of agents that act by inhibiting particular tyrosine kinase enzymes, instead of non-specifically inhibiting rapidly dividing cells. The pharmaceutical forms proposed for these applications were those traditional forms already used for oral administration, such as capsules and tablets, wherein imatinib was administered alone or in association with several other pharmaceutically active ingredients and with the typical excipients of these pharmaceutical forms.

EP1895984 and US20060275372describe a stable nanoparticulate composition of imatinibmesylate, or a salt thereof and at least one surface stabilizer. EP2009008 claims a pharmaceutical composition comprising imatinibmesylate having less than about 0.09% area HPLC percent units of desmethyl-imatinibmesylate and at least one pharmaceutically acceptable excipients.EP2120877 and US2010087444describe a solid dispersion of imatinibmesylate comprising imatinibmesylate and a pharmaceutically acceptable carrier, wherein said carrier is a cellulose derivative.

US2016143850 and EP3019159 describes a granulate composition of imatinibmesylate comprising of imatinibmesylate, binder and of disintegrant.

US2008119479 claims a pharmaceutical composition which comprises ZD6474 or a pharmaceutically acceptable salt thereof, and imatinib, in association with a pharmaceutically acceptable excipient or carrier.EP2782560 and US2015125534 claims a pharmaceutical powder formulation comprising granules of a tyrosine kinase inhibitor, wherein the granules of the tyrosine kinase inhibitor are coated with an enteric coating, wherein the tyrosine kinase inhibitor is present in an amount of up to 23% by weight based on the total weight of the pharmaceutical powder formulation.

WO2006132930 claims a pharmaceutical combination comprising a pyrimidylaminobenzamide compound andImatinib.

US8653093, US7767688, EP1893213 and WO2006132930 claimsa medicament for the treatment of gastrointestinal stromal tumours by use of a pharmaceutical combination comprising of 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide or a pharmaceutically acceptable salt thereof, and imatinib or a pharmaceutically acceptable salt thereof.

Currently available preparations of Imatinib are solid oral preparations e.g. tablets, and capsules. These preparations have their own disadvantages and limitations, for example they are not suitable for all types of patient populations. Therefore there is an existing need for oral liquid pharmaceutical composition comprising imatinib having improved stability and palatability. Further, the oral liquid preparations are more patient compliant as compared to oral solid dosage forms. Oral solid dosage forms may not be convenient for all types of patient populations (e.g. paediatric patients) to take because of swallowing problems. Therefore it is preferable to administer active ingredient in pharmaceutical liquid dosage form.

OBJECT OF THE INVENTION
It has already been proposed that solid oral preparations as well as other route of administrations are not suitable for all types of patient populations. Therefore the principal object of the present invention is to provide oral liquid pharmaceutical preparation of Imatinib.

Another object of the present invention is to provide oral liquid pharmaceutical preparation of Imatinibwith sweetening agent and flavouring agent to mask the bitter taste of Imatinib and to provide pleasant taste.

A further object of the present invention is to provide process for the preparation of the oral liquid pharmaceutical preparation of Imatinibof the present invention.

A further object of the present invention is to provide use of the composition of the invention in the manufacture of a medicament.

A further object of the present invention is to provide composition of the invention for use as a medicament.

A further object of the present invention is to provide composition for use in the manufacture of a medicament for regulating imatinib to treat chronic myelogenousleukemia (CML), gastrointestinal stromal tumours (GISTs) and a number of other malignancies.

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

There is also provided a method of preparing the liquid pharmaceutical composition comprising Imatinib and one or more pharmaceutically acceptable excipients selected from the group comprising of vehicles, solvents, preservatives, buffering agents, sweetening agents, flavouring agents or combinations thereof.

DETAILED DESCRIPTION OF THE INVENTION
Imatinib, chemically known as N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)-4-[(4-methylpiperazin-1-yl)methyl]benzamide having an empirical formula C29H31N7O and a molecular weight of 493.6 gm/mol has a following structural formula:

Imatinib is a small molecule kinase inhibitor used to treat certain types of cancer. It is currently marketed by Novartis as Gleevec (USA) or Glivec (Europe/Australia) as its mesylate salt, imatinibmesilate (INN). Specifically, it is used for chronic myelogenousleukemia (CML) and acute lymphocytic leukemia (ALL) that is Philadelphia chromosome-positive (Ph+) and certain types of gastrointestinal stromal tumours (GIST), systemic mastocytosis, and myelodysplastic syndrome. It is the first member of a new class of agents that act by inhibiting particular tyrosine kinase enzymes, instead of non-specifically inhibiting rapidly dividing cells. The pharmaceutical forms proposed for these applications were those traditional forms already used for oral administration, such as capsules and tablets, wherein imatinib was administered alone or in association with several other pharmaceutically active ingredients and with the typical excipients of these pharmaceutical forms.

Imatinib is known to be administered through oral route of administration. Oral dosage forms include solid preparations (e.g. tablets, capsules, and powders etc.). Oral liquid preparations are more patient compliant as compared to oral solid dosage forms. Oral solid dosage forms may not be convenient for all types of patient populations (e.g. paediatric patients) to take because of swallowing problems. Therefore it is preferable to administer active ingredient in pharmaceutical liquid dosage form. Further, pharmaceutical agents are known to have strong bitterness which results into a bitter taste and a feeling of numbness in the mouth. Therefore oral solid dosage forms are not preferred for some types of patient population especially paediatric patient population.

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

In one of the further embodiments, the pharmaceutical composition comprises Imatiniband one or more pharmaceutically acceptable excipients selected from the group comprising of vehicles, solvents, preservatives, buffering agents, sweetening agents and flavouring agents or combination thereof.

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

In one of the preferred embodiments, the pharmaceutical composition comprises Imatinib, a vehicle, a solvent, a preservative, a buffering agent, a sweetening agent and a flavouring agent 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 for chronic myelogenousleukemia (CML), gastrointestinal stromal tumours (GISTs) and a number of other malignancies.

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.

Solvents or co-solvents referred in the present invention are water-miscible organic solvents used in liquid drug formulations to increase the solubility of poorly water soluble substances and enhance the chemical stability of a drug. Examples of suitable solvent or co-solvents are but not limited to water, ethanol, polyethylene glycols (PEG), sorbitol, glycerin, propylene glycol and benzyl alcohol. The preferred solvent is glycerin.

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, chlorobutanol etc. and antimicrobial solvents like propylene glycol, chloroform etc.The preferred preservative is sodium benzoate.

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 agent is citric acid monohydrate.

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, acesulfame potassium, liquid glucose, glycerine, sorbitol, liquid maltitol, saccharin sodium and aspartame.The preferredsweetening agent is liquid maltitol, glycerine and acesulfame potassium.

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.

In one of the further embodiments, the present invention provides process for the preparation of the pharmaceutical composition comprising Imatinib and one or more pharmaceutically acceptable excipients selected from the group comprising of vehicles, solvents, preservatives, buffering agents, sweetening agents and flavouring agents or combination thereof.

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.

Examples 1-3: A liquid oral pharmaceutical composition comprising Imatinibmesylateand one or more pharmaceutically acceptable excipients
A general process for the preparation of the liquid oral pharmaceutical compositions comprising Imatinibmesylateand one or more pharmaceutically acceptable excipients was followed. One or more pharmaceutically acceptable excipients are selected from the group comprising of vehicles, solvents, preservatives, buffering agents, sweetening agents and flavouring agents as described herein above. The said general process comprises following steps.

1. Take required quantity of vehicle.
2. Add required quantity of sweetening agent and mix till get homogenously mixed.
3. Add required quantity of preservative and mix till completely dissolved.
4. Add required quantity of Imatinibmesylate and mix till completely dissolved.
5. Add buffering agent till desired pH is attained.
6. Add required quantity of flavoring agent and mix till completely dissolved.
7. Make up the final desired volume with vehicle.
Following examples were prepared following above mentioned general process.
Table 1: Examples of Imatinibliquid compositions
Example 1 Example 2 Example 3
Ingredients Quantity (mg /ml)
Imatinibmesylate (Active ingredient) 80.0 80.0 80.0
Liquid maltitol (Sweetening agent) 300.0 300.0 300.0
Methyl paraben (Preservative) 5.0 5.0 5.0
Ethyl paraben (Preservative) 1.0 1.0 1.0
Citric acid
(Buffering agent) Q.S. to pH 3.0-4.0 Q.S. to pH 4.0-5.0 Q.S. to pH 5.0-5.5
Sodium citrate (Buffering agent) Q.S. to pH 3.0-4.0 Q.S. to pH 4.0-5.0 Q.S. to pH 5.0-5.5
Strawberry flavour (Flavouring agent) 0.1 0.1 0.1
Purified Water (Vehicle) Q.S. to 1 mL Q.S. to 1 mL Q.S. to 1 mL

Table 2: Stability data at different stability conditions of different Imatinib liquid compositions
Batch
No. Stability condition pH Single maximum impurity (unknown)
NMT 0.2% Total impurities
NMT 1.0%
Example 1 Initial 3.48 0.02 0.57
3 M 40ºC/25%RH 3.47 0.02 0.57
3 M 25ºC/40%RH 3.48 0.02 0.57
Example 2 Initial 4.31 0.03 0.66
3 M 40ºC/25%RH 4.31 0.03 0.69
3 M 25ºC/40%RH 4.27 0.03 0.66
Example 3 Initial 5.05 0.02 0.63
3 M 40ºC/25%RH 5.05 0.03 0.65
3 M 25ºC/40%RH 5.03 0.03 0.62

Example 4: A liquid oral pharmaceutical composition comprising Imatinibmesylate and one or more pharmaceutically acceptable excipients further comprisingsolvent
A general process for the preparation of the liquid oral pharmaceutical composition comprising Imatinibmesylate and one or more pharmaceutically acceptable excipients further optionally comprising solvent and an additional sweetening agent was followed. One or more pharmaceutically acceptable excipients are selected from the group comprising of vehicles, solvents, preservatives, buffering agents, sweetening agents and flavouring agents as described herein above. The said general process comprises following steps.

1. Take required quantity of vehicle.
2. Add required quantity of solvent and mix till get homogenously mixed.
3. Add required quantity of sweetening agent and mix till get homogenously mixed.
4. Add required quantity of preservative and mix till completely dissolved.
5. Add required quantity of Imatinibmesylate and mix till completely dissolved.
6. Add buffering agent till desired pH is attained.
7. Add required quantity of flavoring agent and mix till completely dissolved.
8. Make up the final desired volume with vehicle.
Following examplewas prepared following above mentioned general process.
Table 3: Imatiniboral composition with Glycerine
Example 4
Ingredients Quantity(mg /ml)
ImatinibMesylate(Active ingredient) 80.0
Liquid maltitol(Sweetening agent) 100.0
Glycerine(Solvent) 300.0
Sodium benzoate(Preservative) 0.2
Acesulfame potassium(Sweetening agent) 1.0
Citric acid monohydrate(Buffering agent) Q.S. to pH 4.0-5.0
Strawberry flavour(Flavouring agent) 0.1
Purified Water (Vehicle) Q.S. to 1 mL

Table 4: Stability data of Example 4
Stability conditions pH Single maximum unknown impurity
NMT 0.2% Total impurities
NMT 1.0%
Initial 4.44 ND ND
40°C±2°C/
25%RH 1M 4.4 ND ND
2M 4.42 0.08 0.37
3M 4.64 0.06 (RRT 0.68) 0.63
6M 4.6 0.07 (RRT 0.68) 0.69
25°C±2°C/
40±5%RH 3M 4.55 0.06 (RRT 0.68) 0.55
6M 4.55 0.06 (RRT 0.68) 0.57

Table 5: Imatinib Oral Compositions
Example 4
Ingredients Quantity (mg /ml)
ImatinibMesylate (Active ingredient) 1-1000
Liquid maltitol (Sweetening agent) 0-500
Glycerine (Solvent) 0-800
Sodium benzoate (Preservative) 0-1.0
Acesulfame potassium (Sweetening agent) 0.01-10
Citric acid monohydrate (Buffering agent) Q.S. to pH 2.0-7.0
Strawberry flavour (Flavouring agent) 0.01-10
Purified Water (Vehicle) Q.S. to 1 mL

It should be understood that various changes and modifications to the presently preferred embodiments and examples 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.