Claims:We Claim:

1. A stable bilayer composition comprising;
a. Layer A comprising Agomelatine or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients,
b. Layer B comprising Agomelatine or its pharmaceutically acceptable salts, one or more release modifying agent/s and one or more pharmaceutically acceptable excipients.

2. The stable bilayer composition according to claim 1 comprising;
a. Layer A comprising Agomelatine granules and one or more pharmaceutically acceptable excipients,
b. Layer B comprising Agomelatine granules, one or more release modifying agent/s and one or more pharmaceutically acceptable excipients.

3. The stable bilayer composition according to claim 2, wherein Layer A comprises about 50 - 70 % w/w of total Agomelatine granules and Layer B comprises about 30-50 % w/w of total Agomelatine granules.

4. The stable bilayer composition according to claim 3, wherein Layer A comprises about 70 % w/w of total Agomelatine granules and Layer B comprises about 30 % w/w of total Agomelatine granules.

5. The Agomelatine granules according to any of the preceding claims comprises Agomelatine, one or more polymeric carrier and one or more pharmaceutically acceptable excipients.

6. The Agomelatine granules according to claim 5, wherein Agomelatine and one or more polymeric carrier are present in the ratio of about 1:2.

7. A method of preparing agomelatine granules comprising:
a. preparing a drug solution by dissolving Agomelatine and one or more polymeric carrier in one or more suitable solvent/s
b. granulating one or more pharmaceutically acceptable excipients using the drug solution prepared in step a.
c. drying the granules prepared in step b.

8. A method for preparing a stable bilayer composition comprising:
a. preparing Layer A by blending agomelatine granules with one or more pharmaceutically acceptable excipients,
b. preparing Layer B by blending agomelatine granules, one or more release modifying agent/s and one or more pharmaceutically acceptable excipients,
c. compressing Layer A and Layer B prepared in step a. and step b respectively,
d. optionally coating the tablet prepared in step c.

Dated this 11th day of May, 2018

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Dr. Rajiv G. Shah,
Torrent Pharmaceuticals Limited,
Torrent Research Centre,
P.O. Bhat – 382428, Gandhinagar
Gujarat, India
, Description:STABLE PHARMACEUTICAL COMPOSITIONS OF AGOMELATINE

FIELD OF THE INVENTION

Present invention relates to a stable bilayer pharmaceutical composition comprising Agomelatine or its pharmaceutically acceptable salts. Invention also relates to process of preparation of said stable bilayer pharmaceutical composition and its use in the treatment of major depressive disorders.

BACKGROUND OF THE INVENTION

Agomelatine, N[2-(7-methoxy-1-naphthyl)ethyl] acetamide, exhibits antidepressant and anxiolytic effects, acting as a potent agonist of melatonergic MT1 and MT2 receptors, as well as a selective antagonist of 5-HT2C receptors that does not affect serotonin release.

Agomelatine is known to have various polymorphic forms such as Form I, II, III, IV, V, and VI as described in patent applications WO2011128413, WO2005077887, WO2007015003, WO2007015002, WO2007015004 and WO2009095555 respectively. Agomelatine is available in the market as Valdoxan® and Thymanax®, having content of 25 mg by Servier. Other patent applications such as WO2013120463, WO2012130837, WO2012093402, WO2014095818, IN1653/CHE/2011 disclose stabilized amorphous form of Agomelatine by preparing solid dispersion or solid solution of Agomelatine and one or more pharmaceutical excipients using various processes, which results in formation of amorphous form of Agomelatine.

Thus, there remains a major challenge of polymorph stabilization of Agomelatine and formulation of a stable pharmaceutical composition comprising Agomelatine.
Additionally, Agomelatine also has disadvantage of having very low bioavailability and as a consequence, it shows a large inter subject variability. WO 2014041015 discloses that this less bioavailability of Agomelatine is in part related to the solubility of Agomelatine in water, which is less than 0.15 mg/ml at 25 °C.

Apparently, there are many solutions suggested in prior art for improvement in stability of polymorphs or improvement of dissolution of Agomelatine and thus its bioavailability, however there still exists a need to provide stable composition of agomelatine with desired dissolution and bioavailability.

Present invention provides a novel bilayer composition comprising Agomelatine, wherein Agomelatine has polymorphic stability and simultaneously provides uniform and desirable release profile of Agomelatine.

SUMMARY OF THE INVENTION
The present invention provides a stable bilayer composition comprising
a. Layer A comprising Agomelatine or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients,
b. Layer B comprising Agomelatine or its pharmaceutically acceptable salts, one or more release modifying agent/s and one or more pharmaceutically acceptable excipients.

Another aspect of the present invention provides a stable bilayer composition comprising
a. Layer A comprising Agomelatine granules and one or more pharmaceutically acceptable excipients,
b. Layer B comprising Agomelatine granules, one or more release modifying agent/s and one or more pharmaceutically acceptable excipients.

The present invention also provides a preparation method for stable bilayer composition comprising-
a. preparing Layer A by blending agomelatine granules with one or more pharmaceutically acceptable excipients,
b. preparing Layer B by blending agomelatine granules, one or more release modifying agent/s and one or more pharmaceutically acceptable excipients,
c. compressing Layer A and Layer B prepared in step a. and step b respectively,
d. optionally coating the tablet prepared in step c.

BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 XRPD diffractogram for Agomelatine bilayer tablet (Initial).
FIG. 2 XRPD diffractogram for Agomelatine bilayer tablet (Alu-Alu with desiccant lining at 40°C and 75 % RH for 1 month).
FIG. 3 Comparative dissolution profile of marketed tablet (Valdoxan®) Vs Agomelatine bilayer tablet of present invention.

DETAILED DESCRIPTION OF THE INVENTION
The following paragraphs detail various embodiments of the invention. For the avoidance of doubt, it is specifically intended that any particular feature(s) described individually in any one of these paragraphs (or part thereof) may be combined with one or more other features described in one or more of the remaining paragraphs (or part thereof). In other words, it is explicitly intended that the features described below individually in each paragraph (or part thereof) represent important aspects of the invention that may be taken in isolation and combined with other important aspects of the invention described elsewhere within this specification as a whole, and including the examples and figures. The skilled person will appreciate that the invention extends to such combinations of features and that these have not been recited in detail here in the interests of brevity.

The use of the terms “a” and "an” and "the” and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

Present invention relates to a novel approach of providing the stable bilayer pharmaceutical composition of Agomelatine providing polymorphic stability and desired dissolution profile and thus bioavailability.

The first embodiment of the present invention provides a stable bilayer composition comprising
a. Layer A comprising Agomelatine or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients,
b. Layer B comprising Agomelatine or its pharmaceutically acceptable salts, one or more release modifying agent/s and one or more pharmaceutically acceptable excipients.

A preferred embodiment of the present invention provides a stable bilayer composition comprising
a. Layer A comprising Agomelatine granules and one or more pharmaceutically acceptable excipients,
b. Layer B comprising Agomelatine granules, one or more release modifying agent/s and one or more pharmaceutically acceptable excipients.

Another embodiment of the present invention provides a stable bilayer composition comprising
a. Layer A comprising Agomelatine granules and one or more pharmaceutically acceptable excipients,
b. Layer B comprising Agomelatine granules, one or more release modifying agent/s and one or more pharmaceutically acceptable excipients, wherein
Layer A comprises about 50-70 % w/w of total Agomelatine granules and Layer B comprises about 30-50 % w/w of total Agomelatine granules.

In a preferred embodiment, Layer A comprises about 70 % w/w of total Agomelatine granules and Layer B comprises about 30 % w/w of total Agomelatine granules.

The Agomelatine granules according to the present invention comprises Agomelatine, one or more polymeric carrier and one or more pharmaceutically acceptable excipients.

The granules according to the present invention may be prepared using known methods for granulation such as wet granulation by high shear granulation (Rapid mixer granulator/RMG) or fluidized bed granulation (FBG) or dry granulation using roller compactor etc. Wet granulation may be aqueous or non-aqueous.

The Agomelatine granules according to the present invention are prepared by a method comprising
a. preparing a drug solution by dissolving Agomelatine and one or more polymeric carrier in one or more suitable solvent/s
b. granulating one or more pharmaceutically acceptable excipients using the drug solution prepared in step a.
c. drying the granules prepared in step b.

The ratio of Agomelatine to the polymeric carrier in the granules ranges from about 5:1 to about of 1:5. Preferably, it ranges from about 3:1 to about 1:3. The most preferable ratio of Agomelatine to polymeric carrier is about 1:2. The granules are prepared by dissolving Agomelatine and polymeric carrier in ethanol, acetone or other suitable solvents or a mixture thereof and sprayed on a one or more pharmaceutically acceptable excipients.

Another aspect of the present invention provides stable bilayer pharmaceutical composition comprising Agomelatine granules as prepared above and pharmaceutically acceptable excipients including filler/s, disintegrant/s, glidant/s and/or lubricant/s.

Another embodiment of the present invention provides a method for preparing a stable bilayer composition comprising
a. preparing Layer A by blending Agomelatine granules with one or more pharmaceutically acceptable excipients,
b. preparing Layer B by blending Agomelatine granules, one or more release modifying agent/s and one or more pharmaceutically acceptable excipients,
c. compressing Layer A and Layer B prepared in step a. and step b respectively,
d. optionally coating the tablet prepared in step c.

The order of steps in the process of preparation of stable bilayer pharmaceutical compositions according to present invention is for the purpose of representation only and should not limit the scope of the embodiments with respect to performance of steps in the mentioned sequence.

Pharmaceutical excipients according to present invention comprises diluent, disintegrant, lubricant, glidant and the like. Compositions according to present invention may optionally further comprises one or more surfactant/s, coloring agent, flavoring agent, preservatives, antioxidants and the like. Example and suitable amount of said optional excipient is known to a skilled person or as given in Handbook of pharmaceutical excipients (sixth edition, 2009).

A diluent according to present invention includes lactose, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, starch, dibasic calcium phosphate, dibasic sodium phosphate, tribasic sodium phosphate; sugars such as dextrose or sucrose; sugar alcohols such as mannitol, sorbitol, xylitol or erythritol; or mixtures thereof. Preferably diluent is lactose, microcrystalline cellulose and/or Pre-gelatinised starch. Pharmaceutical composition comprises diluent in the amount of 5-80 % w/w and preferably 10-60% w/w of the total composition.
A disintegrant according to present invention includes calcium carboxymethyl cellulose and its salt including sodium or calcium salt, crospovidone, cross-linked carboxymethyl cellulose sodium, cross-linked carboxymethyl cellulose calcium, cross-linked polyvinylpyrrolidone, sodium starch glycolate, pregelatinized starch; low substituted hydroxypropyl cellulose; or mixtures thereof. Preferably disintegrant is crospovidone. Pharmaceutical composition comprises disintegrant in the amount of 0-30% w/w and preferably 5-20% w/w of the total composition.

A lubricant according to present invention includes talc, metallic stearate such as magnesium stearate, calcium stearate, zinc stearate; colloidal silicon dioxide, finely divided silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, sodium stearyl fumarate, magnesium trisilicate or mixtures thereof. Preferably lubricant is magnesium stearate. Pharmaceutical composition comprises lubricant in the amount of 0.1-2% w/w and preferably 0.2-1% w/w of the total composition.

A glidant according to present invention includes silica, talc, colloidal silicone dioxide (Aerosil® 200, Syloid®, Cab-OSil®), magnesium trisilicate, cellulose powder, magnesium stearate and corn starch or mixture thereof. Preferably glidant is colloidal silicone dioxide. Pharmaceutical composition comprises glidant in the amount of 0-6% w/w and preferably 0.5-2 % w/w of the total composition.

A polymeric carrier according to present invention includes polyvinyl pyrrolidone (Kollidon 25), copolymer of polyvinylpyrrolidone with polyvinyl acetate (Kollidon VA-64), Soluplus (copolymer of polyvinyl caprolactam, polyvinyl acetate and polyethylene glycol), Kollidon 30 or mixtures thereof. Preferably polymeric carrier is polyvinyl pyrrolidone (Kollidon 25).

A release modifying agent according to present invention includes, cellulose derivatives such as cellulose powder, microcrystalline cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, or mixtures thereof. Preferably release modifying agent is hydroxypropyl methylcellulose. Pharmaceutical composition comprises release modifying agent in the amount of 1-40% w/w and preferably 5-30% w/w of the total composition.

Pharmaceutical compositions prepared according to present invention, comprises Agomelatine in the amount of 0.1-40%, preferably 5-25%, most preferably 10-15% w/w of the total composition.
A stabilized pharmaceutical composition according to present invention is the composition for immediate release, which is in the form of bilayer tablets. A stabilized bilayer pharmaceutical composition of the present invention, in the form of tablet can be obtained by compression molding, for example using a rotary tableting machine or a single punch tableting machine.

A pharmaceutical composition according to present invention may optionally comprise a coating.
Coating according to present invention may be functional or non-functional coating, preferably coating is non-functional coating.

Non-functional coating comprises a film forming polymer and one or more excipients suitable for said coating, which may be selected from film former, plasticizer, opacifier, coloring agent, glidant etc. Example and suitable amount of said coating excipient is known to a skilled person or as given in Handbook of pharmaceutical excipients (sixth edition, 2009).

Another embodiment of present invention provides use of the stable bilayer pharmaceutical composition prepared according to present invention for the treatment of major depressive disorders.

The prepared bilayer film-coated tablet can be packaged into Alu-Alu blister pack or PVC blister pack. The packages Alu-Alu blister pack protected by a desiccant lining or PVC PCTFE-Polychlorotrifluoroethylene (Aclar®) can be used. The stability tests were conducted for Agomelatine bilayer tablet of the present invention with Alu/Alu Blister with desiccant lining and found that the Agomelatine polymorphic form is stable under 40°C and 75 % RH for 1 month as presented in Figure 1 and 2.

X-ray powder diffraction pattern (XRPD) of the composition prepared according to the present invention was recorded with a PANalyical XPert PRO X-Ray Diffractometer using CuKal radiation and measured in reflection mode in the 2?-range of 2-40° using an X'celerator detector.

It has been found that the inventive process of the present invention provides advantage compared to the prior art disclosed process to use Agomelatine or its pharmaceutically acceptable salt thereof.

The invention is illustrated further by the following examples, which are provided for illustrative purposes and are not intended to be construed as limiting the invention in scope or spirit to the specific formulations described in them.
Example 1
Table 1: Agomelatine formulation (Bilayer Coated Tablet)
Sr. No. Ingredients Qty/Tab (mg) (%w/w)
Intragranular
1 Microcrystalline Cellulose
(Avicel PH 112) 59.35
Drug binder solution
2 Agomelatine (Form I) IH 25.00 -
3 Povidone (K-25) 50.00 -
4 Ethanol Q.S. -
5 Acetone Q.S. -
Total 134.35 -
Layer A
1 Dried Granules 94.05 64.86
2 PG Starch 13.00 8.97
3 Lactose 10.55 7.28
4 Crospovidone (XL10) 25.00 17.24
5 Colloidal anhydrous silica 1.60 1.10
6 Magnesium Stearate 0.80 0.55
Total 145.00 100.00
Layer B
1 Dried Granules 40.31 53.75
2 Lactose 19.09 25.45
3 Hydroxypropyl methylcellulose (K100 LVCR) 14.00 18.67
4 Colloidal anhydrous silica 1.00 1.33
5 Magnesium Stearate 0.50 0.67
6 Iron oxide Yellow (Color) 0.10 0.13
Total 75.00 100.00
Core Total 220.00
Coating
1 Opadry Yellow 03G520034 5.00 2.22
2 Isopropyl alcohol Q.S. -
3 Dichloromethane Q.S. -
Total weight 225.00 -

Process for the preparing Agomelatine bilayer tablet:
Drug solution was prepared by dissolving Povidone K-25 in acetone and ethanol anhydrous mixture (5:1), followed by addition of Agomelatine under stirring until clear solution was obtained. The prepared drug solution was sprayed on Microcrystalline Cellulose by top spray assembly in FBP and the granules were dried The obtained dried granules were divided into two parts i.e. 70% and 30% of total quantity.
Layer A preparation:
Agomelatine granules (70% of total granules) as obtained were blended with excipients such as lactose monohydrate, crospovidone, colloidal silicon dioxide and pregelatinized starch and the blend was lubricated with magnesium stearate.
Layer B preparation
Agomelatine granules (30% of total granules) as obtained were mixed with excipients which include lactose monohydrate, colloidal silicon dioxide, iron oxide yellow and Hydroxypropyl methylcellulose and the blend was lubricated with magnesium stearate.

The blend for Layer A and Layer B obtained above was compressed on a compression machine fitted with suitable punches & dies into bilayer tablets. Optionally, the compressed tablets were coated as with Opadry dispersion.

In vitro dissolution study of immediate release bilayer tablet of the present invention and marketed tablet (Valdoxan®) of Agomelatine was performed with USP type II (Paddle) method at 50 rpm in 900 ml 0.01 N HCL at 37°C and results are presented in the Table 2 and Figure 3, respectively.

Another embodiment of present invention provides immediate release solid dosage forms comprising Agomelatine that provides the in vitro dissolution of more than 80% of the Agomelatine within the first 60 minutes and 98% with in the 240 min (4 hrs), which is comparable to the marked product (Valdoxan®)

Table 2: Comparative dissolution profile of marketed product (230367/ VALDOXAN®) and bilayer tablets of present invention
Time (min.) 0 5 10 15 20 30 45 60 90 120 180 240 300
Valdoxan® (Lot no. 230367) 0 11 38 55 64 75 82 86 90 91 93 93 94
Bilayer Tablet (According to Example 1) 0 11 34 52 65 77 81 84 89 94 97 98 98