FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
Complete Specification [See Sections 10 and rule 13]
Title: Sustained release pharmaceutical composition of Agomelatine
Applicant: (a) Astron Research Ltd
(b) Company Registered under Indian Company ACT
(c) 10th Floor. Premier House Bodakdev. Opp. Gurudwara Sarkhej - Gandhinagar Highway Ahmedabad 380054
Gujarat, India.
The following specification particularly describes the invention and the manner in which it is to be preformed describes the invention:

FIELD OF THE INVENTION
This present invention relates to sustained release pharmaceutical composition of Agomelatine. The invention is particularly suitable for once-a-day solid oral pharmaceutical dosage forms which release therapeutically effective amount of the active ingredient over an extended time period. Further, the present invention relates to process for the preparation of the same.
BACKGROUND OF THE INVENTION
Agomelatine is a new agent with a unique pharmacological outline, as it is the first melatonergic antidepressant. The chemical name for agomelatine is N-[2-(7-methoxy-1-naphthyf) ethyl] acetamide with the following structural formula:

Agomelatine occurs as a white or white alike crystal powder or supplied as a crystalline solid. The molecular formula is C15H17NO2 and the molecular weight is 243.301
Agomelatine has potential role in the treatment of patients with major depressive disorder (MDD). Agomelatine has a new pharmacological mechanism of action, which combines melatonin MTI and MT2 agonist properties with a serotonin 5-HT2C antagonist effect.
Agomelatine is a structural analog of melatonin and was developed by the European pharmaceutical company Servier Laboratories Ltd. Agomelatine was first approved

for clinical use in the European Union in 2009, where it is marketed under the names Valdoxan™ orThymanax™.
Agomelatine. its preparation and its use in therapeutics have been described in European Patent Specifications EP0447285 and EP1564202.
If not disclosed specifically. "Agomelatine'' is understood to mean agomelatine. or its hydrates, crystalline forms and addition salts with a pharmaceutically acceptable acid or base.
Agomelatine can be administered by the oral route or. more specifically, by the enteral route in the form of immediate-release tablets to be swallowed with half a glass of water. These agomelatine tablets are useful, especially in treating major depression, seasonal affective disorder, generalized anxiety disorder, obsessional compulsive disorder, bipolar disorders, sleep disorders, cardiovascular pathologies. pathologies of the digestive system, insomnia and fatigue due to jet-lag, appetite disorders and obesity, and any pathology associated with deregulation of circadian rhvthms.
Pharmacokinetic studies in humans have shown that the bioavailability of Agomelatine by the oral route is low compared to the parenteral route and varies for one and the same individual and from one individual to another. Mean plasma half-life of agomelatine is between 1 and 2 hours and the clearance is high (about 1.100 ml/min). Agomelatine was rapidly and almost completely absorbed after oral administration, but with a low absolute bioavailability caused by a high level of first-pass metabolism.

Also, the low bioavailability of agomelatine and the variations in inter- and intra-individual concentrations led to the search for a new formulation allowing those problems to be solved. In the prior art, many techniques have been used to provide pharmaceutical compositions of agomelatine in order to maintain therapeutic levels of medicaments. Some of pharmaceutical composition of agomelatine described in prior art are as follows;
A solid orodispersible pharmaceutical composition of agomelatine described in the patent application EP1427724 was therefore developed containing agomelatine and granules consisting of lactose and starch dried by co-atomisation and marketed under the name STARLAC®.
The orodispersible tablets make it possible to deliver the active ingredient into the oral cavity and, more specifically, into the sublingual cavity in less than three minutes. Dissolution of the active ingredient in the saliva and then absorption via the mucous membranes of the oral cavity and. more specifically, the sublingual mucous membrane, and rapid passage into the blood make it possible to avoid presystemic degradation and the hepatic first-pass effect. Accordingly, bioavailability is very clearly improved with much lower variability and rapid appearance of the active ingredient in the blood.
However, it quickly became apparent that this formulation had a drawback due to the agomelatine, which causes a pronounced sensation of irritation in the mucous membranes of the oral cavity.
When the sublingual route is specifically targeted, this stinging effect is exacerbated because of the high local concentrations of agomelatine. the end result of which is very poor patient acceptability.

PCT Patent Application WO2007/068829 discloses solid pharmaceutical composition composed of a centra! core or central layer containing agomelatine and excipients allowing an orodispersible formulation to be obtained, and an orodispersible coating optionally containing a counter-irritant.
CN101152143A discloses solid pharmaceutical composition, comprising an active ingredient agomelatine and nonionic hydrophilic surfactant. Such a combination improves the human bioavailability of agomelatine. Although invention of CN101152143 have a certain effect improving bioavailability, but only by such a method does not solve the fundamental problem.
Currently the recommended dose of agomelatine is 25 mg once daily taken orally at bedtime, if there is no improvement of symptoms, the dose may be increased to 50 mg once daily i.e. two 25 mg tablets, taken together at bedtime. In addition. administration of agomelatine 25 mg daily composition has several side effects like distal paresthesias, abdominal cramps; sleep walking, nausea, fear, hard to awaken & nightmares.
Thus there is still an existing and continual need to develop once daily sustained release pharmaceutical composition have possible benefits over Agomelatine 25 mg immediate release like improved patient compliance. In addition, sustained release pharmaceutical composition of agomelatine also decreases the side effects by suppressing the rapid rise drug level in blood. The inventors of the present invention address the need to provide sustained release pharmaceutical composition of agomelatine provide more uniform effect over an extended time period to overcome the above mentioned problems.

OBJECTS OF THE INVENTION
The object of the present invention is to provide a sustained release pharmaceutical composition comprises of agomelatine and pharmaccutically acceptable excipient(s).
Another object of the present invention is to provide a sustained release pharmaceutical composition comprises of agomelatine and sustained release component with pharmaceutically acceptable excipient(s).
Another object of the present invention is to provide a sustained release pharmaceutical composition of agomelatine comprising agomelatine and sustained release component with pharmaceutically acceptable excipients, wherein sustained release component comprises of polymer(s) coating and/or polymer(s) matrix.
Another object of the present invention is to provide a sustained release pharmaceutical composition of agomelatine wherein the release of the therapeutic effective amount of agomelatine over an extended time period.
Another object of the present invention is to provide a sustained release pharmaceutical composition of agomelatine wherein the release of the therapeutic effective amount of agomelatine is up to 12 hour period.
Another object of the present invention is to provide a sustained release pharmaceutical composition of agomelatine comprising an in-vitro dissolution profile ranging between 0.1 to 10% in one hour, 10-25% in two hours, 35 to 50% in six hours and 50 to 85% in eight hours, and more than 80% after 12 hours, wherein the dissolution profile is determined using a USP type 2 (paddle) dissolution system at 75 RPM at a temperature of 37±0.5°C in 900ml of dissolution medium.

Another object of the present invention is to provide a process for the preparation of sustained release pharmaceutical composition comprising of agomelatine and
pharmaceutically acceptabfe excipient(s).
Another object of the present invention is to provide a process for the preparation of sustained release pharmaceutical composition comprising of agomelatine and sustained release component with pharmaceutically acceptable excipient(s).
Another object of the present invention is to provide a sustained release pharmaceutical composition of agomelatine to improve patient compliance and adherence.
Another object of the present invention is to provide a sustained release pharmaceutical composition of agomelatine which reduces the side effects associated with agomelatine.
Another object of the present invention is to provide a sustained release pharmaceutical composition of agomelatine for the treatment of major depression, anxiety disorder, sleep disorders, obsessional compulsive disorder and bipolar disorders.
SUMMARY OF THE INVENTION
The present invention relates to sustained release pharmaceutical composition comprising agomelatine and sustained release component with pharmaceutically acceptable excipient(s), which provides possible benefits like patient compliance & reduce side effects. Further the present invention provides a therapeutic effective

steady state concentration of agomelatine over an extended lime period, preferably up to 12 hour.
DETAILED DESCRIPTION
Unless otherwise indicated, terms in this specification are intended to have their ordinary meaning in the relevant art.
The inventors of the present invention have surprisingly found that it is possible to develop a sustained release pharmaceutical composition of agomelatine which are suitable for once daily administration release a therapeutically effective amount of the active ingredient over an extended time period,
The term "sustained release" as used hereinbefore and throughout the description refers (o that the therapeutically active medicament is released from (he formulation at a controlled rate such that the therapeutically effective amount of active pharmaceutical ingredient is maintained in the blood plasma over an extended period of time to cause the sustained action of the drug, preferably up to 12 hour. Sustained release can be used interchangeably with prolonged release, extended release, controlled release, and modified release, slow release and other such dosage forms.
Further the sustained release pharmaceutical composition according to present invention comprises agomelatine and sustained release component with pharmaceutically acceptable excipient(s).
The composition of the present invention preferably contains agomelatine in an amount of form about 10% to about 50% by weight of the total composition. Agomelatine can be present in crystalline form or amorphous form.

According to present invention sustained release component may be polymer matrix and/or polymer coating.
Suitable polymer matrix material and/or polymer coating materia! may include one or more water soluble and water insoluble polymer(s), waxes, oil, fats or mixtures
thereof.
According to one embodiment of the invention suitable polymer matrix material and/or polymer coating materia! include, for example, waxes e.g.. carnauba, bees wax, paraffin wax. ceresine, shellac wax, fatty acids, and fatty alcohols, oils, hardened oils or fats e.g., hardened rapeseed oil, castor oil. beef tallow, palm oil. and soya bean oil or mixtures thereof and other materials known to one of ordinary skill in the art.
Water soluble polymer(s) includes but not limited to any water soluble substance or polymer which includes but not limited to methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose, sodium carboxymethylcellulose, polyethylene oxides, polyethylene glycols, chitosan. gums, starch derivatives, polyurethanes, galactomannans, polysaccharides, polyalcohols. acrylic acid or acrylamide derivatives and the like. The preferred hydrophilic polymer is hydroxypropyl methylcellulose or any commercially available grade thereof such as Methocel.
Water insoluble polymer(s) includes but not limited to any water insoluble substance or polymer which includes but not limited to ethyl cellulose, glycerol palmitostearate. beeswax, glycowax, carnauba wax. hydrogenated vegetable oil,

glycerol monostearate, stearylalcohol, glyceryl behenate, polyanhydrides, methyl acrylates and the like.
Sustained release component may further comprise one or more pharmaceutical^ acceptable excipient(s) selected from fillers, diluents, binders, disinlegrants, lubricants, glidants, surfactants, colorants, sweeteners, plasticizers. solvent and other suitable excipients or mixtures thereof. One excipient can perform more than one function.
Fillers or diluents, may be selected from, but are not limited to, microcrysialline cellulose, starch, pregelatinized starch, dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose, lactose, xylitol, sorbitol, calcium carbonate, calcium phosphate dibasic or tribasic, calcium sulphate, and the like and other materials known to one of ordinary skill in the art and combinations thereof.
Binders may be selected from, but are not limited to, starches, Processed starch, microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, sodium carboxy methyl cellulose; acacia, alginic acid, guar gum. liquid glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinyl pyrrolidone, poly-N-vinyl amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth,.combinations thereof and other materials known to one of ordinary skill in the art and mixtures thereof.
Disintegrants may be selected form, but are not limited to, croscarmellose sodium, sodium starch glycolate. pregelatinized starch, sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, and the like and other materials known to one of ordinary skill in the art and combinations thereof.

Lubricants may be selected from, but are not limited to, those conventionally known in the art such as Mg, Al or Ca or Zn stearate, glyceryl behenate. mineral oil. sodium stearyl fumarate. stearic acid, talc, and the like and other materials known to one of ordinary skill in the art and combinations thereof.
Glidants may be selected from, but are not limited to, silicon dioxide, magnesium trisiiicate, powdered cellulose, starch, talc, tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel and other materials known to one of ordinary skill in the art and combinations thereof.
Surfactants may be selected from but are not limited to diocty! sodium sulfosuccinate (DSS), triethanolamine. polyoxyethylene. sorbilan and poloxalkot derivatives, quaternary ammonium salts or other materials known to one of ordinary skill in the art and combinations thereof.
Colorants may be selected from, but not limited to one or more of non-water soluble lake pigments; neutral pigments; yellow ferric oxide; red ferric oxide; black iron oxide and the like and other materials known to one of ordinary skill in the art and combinations thereof.
Plasticizers may include, but not limited to one or more of polyols such as glycerol, propylene glycol, polyethylene glycol (PBG). urea, or other known plasticizers such as trielhyl citrate, dibutyl or dimethyl phthalate or water.
Further, the sustained release pharmaceutical composition according to the present invention can be dispensed as a dosage form for oral administration. Preferable dosage forms include pellets, beads, granules, tablets, capsules, sachets, caplets and like thereof for oral administration.

In another embodiment of the present invention is to provide a process for the preparation of sustained release pharmaceutical composition of agomelatine. According to present invention the sustained release pharmaceutical composition may be prepared by process known to the person having ordinary skilled in the art of the pharmaceutical technology such as direct compression, wet granulation, dry granulation, slugging, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion-spheronization, spray-drying and solvent evaporation.
in one preferred embodiment of the present invention is to provide a process for the preparation of sustained release pharmaceutical composition of agomelatine comprising following steps:
(a) preparing a granulation fluid by dispersing binder in a solvent;
(b) sifting agomelatine, one or more fillers and sustained release component to obtain a mixture
(c) granulating the mixture obtained in step (b) with the granulation fluid obtained in step (a) to form a wet mass;
(d) drying the wet mass obtained in step (c) and then blending with glidant.
(e) lubricating the blended granules obtained in step (d) and finally compressed into tablets; and
(f) optionally coating the tablet obtained in step (e).
In another preferred embodiment of the present invention to provide a process for the preparation of sustained release pharmaceutical composition of agomelatine comprising following steps:
(a) preparing a granulation fluid by dispersing binder in a solvent;
(b) sifting agomelatine. one or more pharmaceutical!)' excipient(s) to obtain a mixture;

(c) granulating the mixture obtained in step (b) with the granulation fluid obtained in step (a) to form a wet mass;
(d) drying the wet mass obtained in step (c) and then blending with glidant:
(e) lubricating the blended granules obtained in step (d) lo obtain drug core:
(f) prepare the sustained release coating solution with polymer and pharmaceutical excipicnts in solvent;
(g) coating the drug core of step (e) with sustained release coating solution of step (f) and then compressed the coated granules into tablets.
All excipients can be used at levels well known to the persons skilled in the art. Solvents may be used in present invention include all the solvents well known in the art or their mixtures thereof. Examples of the solvents used for preparing the granulation fluid or coating solution are selected form the group comprising ethyl alcohol, isopropyl alcohol, n-butyl alcohol, acetone, aceionitrile. chloroform, methylene chloride, purified water or mixture thereof.
The pharmaceutical composition may further be coated with film forming polymers and one or more pharmaceutical!}' acceptable excipient(s). using techniques well known in the art. Pharmaceutical^ acceptable excipients(s) may be selected from described herein before.
Further the sustained release pharmaceutical composition according to present invention comprises optionally immediate release component with pharmaceutical^ acceptable excipient(s). Pharmaceutical!}' acceptable excipients(s) may be selected from described herein before.

The sustained release composition of the present invention is suitable for treatment of major depression, anxiety disorder, sleep disorders, obsessional compulsive disorder and bipolar disorders.
EXAMPLES
The present invention has been described by way of example only. It is to be recognized that modifications falling within the scope and spirit of the claims, 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 scope of the invention is in no manner limited by the disclosed example.
Representative example:

S.No. Ingredients %w/wofthe composition
1 Agomelatine 10-50
2 Fillers 20-80
3 Sustained release component 1-20
4 Binder 2-10
5 Glidant 0-1
6 Lubricant 0-1
7 Solvent/Purified water q.s.
Total 100
Procedure:
Polymer matrix tablets
Granulating a blend of Agomelatine. fillers and sustained release component with granulation fluid prepared by dispersing binder in purified water. The obtained

granules are dried, screened and blended with glidanl and lubricant and then lubricated granules compressed into tablets.
Polymer coated tablets
Sifting the agomelatine with one or more pharmaceutically acceptable excipients and granulating the said sifted mixture with granulating fluid prepared by dispersing binder in purified water. The obtained granules blended with glidant and lubricant. Preparing the sustained release solution by dissolving the polymer and pharmaceutical acceptable excipients in solvent and coal the said solution on to the lubricated granules and then coated granules compressed into tablets.
In-vitro dissolution profile:
Two step dissolution medium were used for the targeted in vitro dissolution profile of sustained release pharmaceutical composition of Agomelatine i.e. (a) Dissolution medium: 1.2 pH (0.1 N HCI); Volume 900ml. 75 RPM Paddle; (b) Dissolution medium6.8 pH (Phosphate buffer); Volume 900ml. 75 RPM Paddle. According to present invention, the targeted in vitro dissolution profile of present invention can be represented as below:

S.No. Time (hr) % drug release
1 1 5-10
2 2 10-25
3 4 35-50
4 8 50-85
5 12 More than 80

Example 1

S.No. Ingredients mg/tah
1 Agomelatine 50
2 Lactose monohydrate 88.5
3 HPMC K4M 8
4 Povidone K-30 2
5 Purified water q.s.
6 Isopropyl alcohol q.s.
7 Colloidal anhydrous silica 0.5
S Magnesium stearate 1
Total 150
Brief manufacturing procedure:
1. A granulation fluid is prepared by dispersing povidone in water.
2. Agomelatine, Lactose monohydrate and hydroxypropyl mcthylceliulose are sifted to obtain a mixture.
3. The mixture obtained in step 2 is granulated with the granulation fluid obtained in step I.
4. The granules obtained in step 3 are dried, screened and blended with colloidal anhydrous silica.
5. The granules obtained in step 4 then lubricated with magnesium stearate to obtained lubricated granules.
6. The lubricated granules obtained in step 5 then compressed into tablets.

Example 2 Drug core

S.No. Ingredients mg/tab
] Agomelatine 50
2 Lactose tnonohvdrate 96.5
3 Povidone K-30 2
4 Purified water q.s.
5 Colloidal anhydrous silica 0.5
6 Magnesium stearate 1
Total 150
Sustained release coating composition-

S.No. Ingredients mg/tab
I Ethyl cellulose (100 CPS) 16.00
2 Dibutyl sebacate 4.0
3 Povidone K90 5.0
4 Ethanol q.s.
5 Purified Water q.s.
Total 25.00
Brief manufacturing procedure: Preparation of drug core:
1. A granulation fluid is prepared by dispersing povidone in water.
2. Agomelatine and Lactose monohydrate are sifted to obtain a mixture.
3. The mixture obtained in step 2 is granulated with the granulation fluid obtained in step I.

4. The granules obtained in step 3 are dried, screened and blended with colloidal anhydrous silica.
5. The granules obtained in step 4 then lubricated with magnesium stearate to obtained drug core.
Preparation of sustained release coating composition:
1. Dissolve dibutyl sebacate in ethanol
2. Added ethyl cellulose and povidone to above solution of step I.
3. Added purified water to above solution of step 2 with continuous stirring until clear solution.
Preparation of coated tablet:
1. Coat the sustained release coating composition on drug core and then compressed into tablets.
Jn-vitro dissolution study:
In-vitro dissolution profile obtained according to example 1 and example 2 is as follows:
(a) Dissolution medium: 1.2 pH (0.1 N HCI); Volume 900ml, 75 RPM Paddle

S.No. Time (hr) Average drug release (%) (Min-Max)

Example 1 Example 2
1 1 9(8-10) 7 (6-8)
2 2 21 (18-24) 15(M-I7)
3 4 42(36-48) 40(38-45)
4 8 81 (74-88) 75 (70-77)
5 12 101 (98-103) 100(98-102)

(b) Dissolution medium: 6.8 pH (Phosphate buffer); Volume 900ml, 75 RPM Paddle

S.No. Time(hr) Average drug release (Min-Max)

Example 1 Example 2
1 1 8(7-10) 6 (5-7)
2 2 18(14-23) 13(11-15)
3 4 35 (28-42) 38 (37-42)
4 8 66 (55-76) 66 (60-68)
5 12 93 (86-99) 95 (92-98)
The in-vitro dissolution profile of sustained release pharmaceutical composition of Agomelatine as disclosed in example 1 and example 2 matches with the desired dissolution profile according to the present invention.

We claim;
1. A sustained release pharmaceutical composition comprising agomelatine and sustained release component with pharmaceutical!)' acceptable excipient(s).
2. The sustained release pharmaceutical composition of claim 1 wherein sustained release component comprises of polymer(s) coating and/or pofymer(s) matrix optionally with pharmaceutical!}'' acceptable excipients.
3. The sustained release pharmaceutical composition of claim 1. wherein the polymer matrix material and/or polymer coating material may include one or more water soluble and water insoluble polymer(s). waxes, oil, fats or mixtures thereof.
4. The sustained release pharmaceutical composition of claim 1. wherein the polymer matrix comprises hydroxypropyl methyl cellulose.
5. The sustained release pharmaceutical composition of claim I. wherein the polymer coating comprises ethyl cellulose.
6. The sustained release pharmaceutical composition of claim I, comprising the agomelatine in an amount within the range of about 10% to about 50% of the total weight of the composition.
7. The sustained release pharmaceutical composition of claim 1, wherein therapeutic effective amount of agomelatine release up to 12 hour period.

8. The sustained release pharmaceutical composition of claim 1, having agomelatine in vitro dissolution profile ranging between 0.1 to 10% in one hours. 10 to 25% in two hours, 35 to 50% in six hours and 50 to 85% in eight hours, and more than 80% after 12 hours, wherein the dissolution profile is determined using a USP type 2 (paddle) dissolution system at 75 RPM at a temperature of 37±0.5°C in 900ml of dissolution medium.
9. A process for the preparation of sustained release pharmaceutical composition according to claim 1 comprising following steps:

(a) preparing a granulation fluid by dispersing binder in a solvent;
(b) sifting agomelatine, one or more fillers and sustained release component to obtain a mixture
(c) granulating the mixture obtained in step (b) with the granulation fluid obtained in step (a) to form a wet mass;
(d) drying the wet mass obtained in step (c) and then blending with glidant.
(e) lubricating the blended granules obtained in step (d) and finally compressed into tablets; and
(f) optionally coating the tablet obtained in step (e).
10. A process for the preparation of sustained release pharmaceutical
composition according to claim. 1 comprising following steps:
(a) preparing a granulation fluid by dispersing binder in a solvent;
(b) sifting agomelatine. one or more pharmaceutical^ excipient(s) to obtain a mixture;
(c) granulating the mixture obtained in step (b) with the granulation fluid obtained in step (a) to form a wet mass;
(d) drying the wet mass obtained in step (c) and then blending with glidant:
(e) lubricating the blended granules obtained in step (d) to obtain drug core;

(f) prepare the sustained release coating solution with polymer and pharmaceutical excipients in solvent;
(g) coating the drug core of step (e) with sustained release coating solution of step (f) and then compressed the coated granules into tablets.