DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)
&
THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(See section 10; rule 13)

“PHARMACEUTICAL COMPOSITION OF VORTIOXETINE HYDROBROMIDE”

ALEMBIC PHARMACEUTICALS LIMITED
An Indian Company
Alembic Campus, Alembic Road, Vadodara-390 003,
Gujarat, India.

The following specification describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition of Vortioxetine Hydrobromide and method for preparing the pharmaceutical composition containing Vortioxetine Hydrobromide.

BACKGROUND OF THE INVENTION
Vortioxetine is an antidepressant medication that is prescribed to treat depression. It is believed to work to relieve depression by increasing serotonin concentrations in the brain, by inhibiting its reuptake in the synapse and by modulating (activating certain receptors while blocking, or antagonizing, others) certain serotonin receptors. Vortioxetine Hydrobromide in the form of ß-form of tablets is approved in US under the brand name TRINTELLIX®.

Vortioxetine HBr is known chemically as 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine, hydrobromide. The empirical formula is C18H22N2S, HBr with a molecular weight of 379.36 g/mol. The structural formula is:

U.S. Patent No, 7,144,884 (the '884 patent) discloses vortioxetine or its salt thereof.

U.S. Patent No. 8,476,279 discloses pharmaceutical composition comprising the compound 1-[2-(2,4-dimethylphenylsulfanyl) phenyl] piperazine or a pharmaceutically acceptable acid addition salt thereof, and at least one pharmaceutically acceptable carrier or diluent.

U.S. Patent No. 8,722,684 discloses crystalline form of Vortioxetine Hydrobromide salt with specific XRD Pattern.
U.S. Patent No. 8,598,348 discloses Vortioxetine Hydrobromide isopropanol solvate and process of preparation of Vortioxetine Hydrobromide isopropanol solvate.
U.S. Patent No. 9,499,504 discloses delta form of Vortioxetine Hydrobromide with specific XRD Pattern. It also discloses crystalline monohydrate of Vortioxetine Hydrobromide with specific XRD Patten.

WO2015166379 discloses crystalline form A, Ad, B and C of Vortioxetine Hydrobromide and also discloses a co-precipitate of amorphous Vortioxetine hydrobromide
U.S. Patent No. 8,969,355 discloses method of treating a disease selected from the group consisting of affective disorders, depression, major depressive disorder, anxiety, general anxiety disorder, social anxiety disorder, obsessive compulsive disorder, panic disorder, and panic attacks, the method comprising administering a therapeutically effective amount of a pharmaceutically acceptable salt of Compound I to a patient in need thereof by administering the salt of Compound I is crystalline 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt with specific XRD pattern.

U.S. Publication No. 2016/256398 discloses pharmaceutical composition for oral administration, comprising Compound I or a pharmaceutically acceptable acid addition salt thereof, wherein Compound I is 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine and the composition is adapted so that said compound is not released in the stomach. The said patent application specifically discloses the formulation in the form of sustained release or delayed release formulation.

U.S. Publication No. 2013/0115292 discloses enteric coated tablet of vortioxetine or its salt thereof.

OBJECTS OF THE INVENTION
An object of the present invention is to provide a stable pharmaceutical composition comprising Vortioxetine Hydrobromide which is stable during the prolonged duration.
In another aspect of the present invention is to provide method for the preparation of a pharmaceutical composition comprising Vortioxetine Hydrobromide using dry granulation.
In another aspect of the present invention is to provide a stable pharmaceutical composition comprising Vortioxetine Hydrobromide which is devoid of binder.
In another aspect of the present invention is to provide method for the preparation of a pharmaceutical composition comprising Vortioxetine Hydrobromide and low-substituted hydroxyl propyl cellulose.

DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention relates to a pharmaceutical composition comprising Vortioxetine or its salt thereof and one or more pharmaceutical excipients thereof.
For the purpose of the present invention, Vortioxetine Hydrobromide is used for the development of a pharmaceutical composition.
For the purpose of the present invention, the composition comprises Vortioxetine Hydrobromide in an amount of about 0.01 to 100 mg. The total daily dose is usually in the range of about 0.05-500 mg, and most preferably about 0.1 to 50 mg.
The term “pharmaceutical composition” comprises any solid dosage form, preferably such as tablets, capsules, microparticles, beads, pellets, granules, capsule comprising granules/beads/pellets, MUPS tablet, tablet comprising beads or granules, powder filled capsule. The said dosage forms may be optionally coated with the coating agent wherein the coating materials and colorants are either dissolved or dispersed in a suitable solvent.
As per the preferred embodiment of the present invention, the pharmaceutical composition of Vortioxetine Hydrobromide is formulated in the form of tablets.
One of the purpose of the present invention is to develop a pharmaceutical composition comprises Vortioxetine Hydrobromide and one or more pharmaceutically acceptable excipients.
As per one embodiment of the present invention, the pharmaceutical composition and the dosage forms preferably comprises one or more pharmaceutically acceptable carriers which must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
As per one embodiment of the present invention, one or more pharmaceutical excipients are selected from the group comprising of, but not limited to consisting of diluents/fillers, glidants, disintegrants, lubricants.
As per preferred embodiment, a pharmaceutical composition comprises Vortioxetine Hydrobromide, low-substituted hydroxy propyl cellulose and one or more pharmaceutically acceptable excipients.
For the purpose of the present invention low-substituted hydroxy propyl cellulose is present in 5 to 12 %w/w of total composition.
In one embodiment of the present invention is to provide a stable pharmaceutical composition comprising vortioxetine Hydrobromide and one or more intra-granular diluent and one or more extra-granular diluent.
In one embodiment of the present invention is to provide a stable pharmaceutical composition comprising vortioxetine Hydrobromide and one or more intra-granular diluent and one or more extra-granular diluent which may be same or different.
In another embodiment of the present invention, a stable pharmaceutical composition of vortioxetine Hydrobromide comprises one or more intra-granular diluent which may be same or different to each other.
As per the preferred embodiment, a stable pharmaceutical composition of vortioxetine Hydrobromide comprises intra-granular and extra-granular diluent, wherein intra-granular and extra-granular diluent is same.
As per the preferred embodiment, a stable pharmaceutical composition of Vortioxetine Hydrobromide contains hydrophilic intra-granular and extra-granular diluent.
As per one embodiment of the present invention, diluents/fillers is selected from the group comprising of, but not limited to lactose, lactose anhydrous, microcrystalline cellulose, silicified microcrystalline cellulose (Prosolv SMCC HD 90), sucrose, glucose, fructose, mannitol, sorbitol, xylitol, dextrose, dibasic calcium phosphate, tribasic calcium phosphate, calcium hydrogen phosphate dehydrate, magnesium carbonate, inorganic salts such as calcium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, dextrin/dextrates, maltodextrin, sodium chloride, starch, pregelatinised starch, magnesium oxide or a combination thereof.
As per the preferred embodiment, a stable pharmaceutical composition contains mannitol as intra-granular and extra-granular diluent.
For the purpose of the present invention, ratio of one or more intra-granular diluent to extra-granular diluent is in the range of 1.4 to 2.2.
In another embodiment, a ratio of Vortioxetine Hydrobromide to one or more intra-granular diluent is in the range of 0.2 to 0.6.
In another embodiment, a ratio of Vortioxetine Hydrobromide to extra-granular diluent is in the range of 0.5 to 0.9.
For the purpose of the present invention, a stable pharmaceutical composition comprises Vortioxetine Hydrobromide and an intra-granular and an extra-granular lubricant.
In one embodiment, a stable pharmaceutical composition comprises one or more intra-granular lubricant and one or more extra-granular lubricant.
For the purpose of the present invention, one or more intra-granular lubricant is hydrophobic in nature and extra-granular lubricant is in hydrophilic in nature.
As per the preferred embodiment, a stable pharmaceutical composition of Vortioxetine Hydrobromide comprises hydrophilic extra-granular lubricant.
As per one embodiment of the present invention, hydrophobic lubricant is selected from the group comprising of, but not limited to magnesium stearate, zinc stearate, stearic acid, palmitic acid, myristic acid, sodium behenate, calcium stearate, aluminium stearate, sodium stearate, sodium oleate, sodium benzoate, glyceryl palmitostearate, glyceryl bahenate or combination thereof.
As per the preferred embodiment, a stable pharmaceutical composition of Vortioxetine Hydrobromide comprises Sodium stearyl fumarate as extra-granular hydrophilic lubricant.
For the purpose of the present invention, a ratio of extra-granular lubricant to intra-granular lubricant is in the range of 3 to 7.
For the purpose of the present invention is to provide higher drug release by using hydrophilic excipients in the formulation.
For the purpose of the present invention, the pharmaceutical composition of the present invention comprises intra-granular and/or extra-granular hydrophilic diluent and hydrophilic lubricant so that higher drug release can be achieved.
As per one embodiment of the present invention, glidant is selected from the group comprising colloidal silicon dioxide, calcium silicate and talc or a combination thereof.
For the purpose of the present invention, a pharmaceutical composition comprises of Vortioxetine Hydrobromide and one or more pharmaceutical acceptable excipients, wherein the pharmaceutical composition is further film coated.
As per the preferred embodiment of the present invention, the pharmaceutical composition comprises of Vortioxetine Hydrobromide and one or more pharmaceutical acceptable excipients, wherein the pharmaceutical composition is further film coated.
As per one embodiment of the present invention, the said outer coat is selected from taste masking coats, coats with aqueous moisture barriers and/or oxidative barriers to improve the stability of the composition, and cosmetic coats for example a coat containing coloring agents, sweetening agents and/or flavoring agents in order to provide an elegant and palatable tablet and/or to provide easily distinguishable dose strengths.
As per another embodiment of the present invention, the pharmaceutical composition of Vortioxetine Hydrobromide having different strengths is coated with different colors, so that the different dose strengths are easily distinguished.
For the purpose of the present invention, the outer coat is easily soluble in aqueous media in order to provide that the matrix comes in contact with the surrounding aqueous media via the openings in the coating immediately after administration.
For the purpose of the present invention, film coating in a pharmaceutical composition of Vortioxetine Hydrobromide according to the present invention comprises film former, solvents to dissolve or disperse polymers, plasticizers including internal plasticizing which pertains to the chemical modification of the basic polymer that alters the physical properties of the polymer and external plasticizing that is incorporated with the primary polymeric film former, changes the flexibility, tensile strength or adhesion properties of the resulting film.
For the purpose of the present invention, film former is selected from the group comprising of, but not limited to hydroxyl propyl methyl cellulose (HPMC), polyvinyl alcohol (PVA), ethyl cellulose, Hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), methyl hydroxyl ethyl cellulose (MHEC), polyethylene glycols, polyvinyl pyrrolidone (PVP), waxy materials or combination thereof.
For the purpose of the present invention, solvents to dissolve or disperse polymers are selected from the group comprising of, but not limited to isopropyl alcohol (IPA), methylene chloride, chloroform, methanol, ethanol, ethyl acetate, ethyl lactate, acetone, isopropyl alcohol (IPA), dichloromethane (DCM) or 1,1,1-trichloroethane, water or combinations thereof.
For the purpose of the present invention, plasticizers is selected from the group comprising of, but not limited to internal plasticizing agent comprises glycerol, propylene glycol, PEG 200-6000 grades and external plasticizing agent comprising diethyl phthalate (DEP), dibutyl phthalate (DBP), triethyl citrate (TEC), tributyl citrate (TBC), triacetin or combination thereof.
For the purpose of the present invention, colorant alone or in combination is selected from the group comprising of, but not limited to inorganic materials for light shade and natural coloring materials for dark shade, opaquant extenders which provide more pastel colors and increase film coverage.
For the purpose of the present invention, colorant is selected from the group comprising of, but not limited to inorganic materials like iron oxides and natural coloring materials like anthrocynins, caramel, carotenoids or combinations thereof.
For the purpose of the present invention, opaquant extender is selected from the group comprising of, but not limited to titanium dioxide (TiO2), silicates like talc and aluminum carbonates, carbonates (magnesium carbonate).
For the purpose of the present invention, a stable pharmaceutical composition comprises Vortioxetine Hydrobromide and one or more excipients, wherein the composition is devoid of binder.
As per another embodiment, a pharmaceutical composition comprises Vortioxetine Hydrobromide according to the present invention is formulated by direct compression or dry granulation-roller compaction.
As per the preferred embodiment, a pharmaceutical composition comprises Vortioxetine Hydrobromide according to the present invention is formulated by dry granulation-roller compaction.
For the purpose of the present invention, Vortioxetine Hydrobromide and other excipients like Low substituted hydroxyl propyl cellulose, diluent and lubricant are mixed together in the blender. Compaction is performed by roller compaction to make slugs. Slugs are then milled and granules are obtained. The granules are then mixed with extra-granular excipients. Further it is mixed with extra-granular lubricant and then compressed it in to tablets. The tablets are then further coated.

The following example is intended to be illustrative and non-limiting, and represent specific embodiments of the present invention:

Comparative Example 1:
The composition of Vortioxetine Hydrobromide film coated tablet is disclosed in the Table 1.

Table 1: Vortioxetine Hydrobromide Film coated Tablets
Sr. No Name of the Ingredients % w/w
Intra granular
1 Vortioxetine Hydrobromide 18.15
2 Microcrystalline cellulose 55.6
4 Low-Substituted Hydroxy propyl Cellulose 2.5
5 Magnesium Stearate 0.25
Extra granular
6 Mannitol 20
7 Low-Substituted Hydroxy propyl Cellulose 2.5
8 Colloidal Silicon dioxide 0.25
9 Magnesium Stearate 1.25

Manufacturing process:

Vortioxetine Hydrobromide, Microcrystaline cellulose and Low-substituted Hydroxy Propyl Cellulose and magnesium stearate are blended together. Compaction is done by using roller compaction in 2 cycles to prepare slugs. Simultaneously mill the slugs through inbuilt granulator and collect the granules. Mannitol, Low-substituted Hydroxy Propyl Cellulose and Colloidal Silicon Dioxide is mixed with the granules in the blender. Further, Magnesium stearate is also mixed with the granules in the blender. Compress the lubricated blend in to the tablets and coat the tablets.

The tablets manufactured as per the above process are subjected to dissolution testing by using 900 ml of 0.1 N HCl as dissolution medium in USP II dissolution apparatus at 50 RPM for 45 minutes at 37±0.5°C (n= 6 units). The results of Vortioxetine Hydrobromide release is described in Table 2 and Figure 1.

Table 2: Dissolution Results of Vortioxetine Tablets as per comparative Example 1
Time (minutes) % Drug Release
Mean RSD
10 77 10.0
15 77 9.9
30 79 9.5
45 82 9.7

Example 1:

Vortioxetine Hydrochloride Tablets are manufactured by using intra-granular and extra-granular mannitol as diluent and sodium stearyl fumarate as extra-granular hydrophilic lubricant.

Table 3: Vortioxetine Hydrochloride Film Coated Tablets
Sr. No Ingredients % w/w
Intra granular
1 Vortioxetine Hydrobromide 17.62
2 Microcrystalline cellulose 37.72
3 Mannitol 6.07
4 Low-Substituted Hydroxy propyl Cellulose 4.85
5 Magnesium Stearate 0.24
Extra granular
6 Mannitol 24.27
7 Low-Substituted Hydroxy propyl Cellulose 4.85
8 Colloidal Silicon dioxide 0.24
9 Sodium Stearyl Fumarate 1.21
Coating
10 Opadry Brown 03F565072 2.91
11 Purified Water q.s
Total 100

Manufacturing Process:

Vortioxetine Hydrobromide, Microcrystaline cellulose, Mannitol and Low-substituted Hydroxy Propyl Cellulose and magnesium stearate are mixed and blended. Compaction is done using roller compaction in one cycle to prepare slugs. Simultaneously mill the slugs through inbuilt granulator and collect the granules. Mannitol, Low-substituted Hydroxy Propyl Cellulose and Colloidal Silicon Dioxide are mixed with the granules in the blender. Further, Sodium stearyl fumarate is mixed with the granules in the blender. Compress the lubricated blend in to the tablets and coat the tablets.

The tablets manufactured as per the above process are subjected to dissolution testing by using 900 ml of 0.1 N HCl as dissolution medium in USP II dissolution apparatus at 50 RPM for 45 minutes at 37±0.5°C (n= 6 units). The results of Vortioxetine Hydrobromide release is described in Table 4 and Figure 2.

Table 4: Dissolution Results of Vortioxetine Hydrobromide Tablets as per Example 1
Time (minutes) % Drug release
Mean RSD
10 89 3.2
15 91 2.3
20 92 2.3
30 93 2.5
45 94 2.6

The comparative dissolution of drug release of Comparative Example 1 and Example 1 is as per the Figure 3. The dissolution pattern as per Figure 3 indicates that by using hydrophilic intra-granular and extra-granular mannitol and hydrophilic extra-granular Sodium stearyl fumarate gives higher release of Vortioxetine Hydrobromide.

Comparative dissolution of currently marketed Vortioxetine Hydrobromide Film coated tablets (TRINTELLIX) and the proposed formulation according to the Table 5 and Figure 4.

Table 5: Comparative Dissolution of Trintellix and Tablets formulation of Example 1
Product Trintellix (Vortioxetine) Tablets, 20 mg Tablet Formulation of Example 1, 20 mg
Time (Minutes) % Drug Release
Mean RSD Mean RSD
10 89 8.2 89 3.2
15 94 4.2 91 2.3
20 96 3.0 92 2.3
30 97 2.6 93 2.5
45 98 2.6 94 2.6

. Dated this 3rd October 2018

_______________________
(Patel Dhaval Pinakinbhai)
For Alembic Pharmaceuticals Limited

,CLAIMS:We Claim:

1. A stable pharmaceutical composition comprising Vortioxetine hydrobromide and pharmaceutically acceptable excipients thereof, wherein the stable pharmaceutical composition comprises Low-Substituted Hydroxy propyl Cellulose.

2. A stable pharmaceutical composition according to claim 1, wherein the composition comprises one or more intra-granular and/or extra-granular diluent and one or more intra-granular and/or extra-granular lubricant.

3. A stable pharmaceutical composition according to claim 1, wherein Low-Substituted Hydroxy propyl Cellulose is present in 5 to 12 %w/w of total composition.

4. A stable pharmaceutical composition according to claim 2, wherein the intra-granular and/or diluent is mannitol.

5. A stable pharmaceutical composition according to claim 2, wherein the ratio of one or more intra-granular diluent to extra-granular diluent is in the range of 1.4 to 2.2.

6. A stable pharmaceutical composition according to claim 2, wherein the ratio of Vortioxetine Hydrobromide to one or more intra-granular diluent is in the range of 0.2 to 0.6 and extra-granular diluent is in the range of 0.5 to 0.9.

7. A stable pharmaceutical composition according to claim 2, wherein the intra-granular and/or lubricant is sodium stearyl fumarate.
8. A stable pharmaceutical composition according to claim 2, wherein the ratio of extra-granular lubricant to intra-granular lubricant is in the range of 3 to 7.

9. A stable pharmaceutical composition comprising Vortioxetine hydrobromide and pharmaceutically acceptable excipients thereof, wherein the stable pharmaceutical composition is devoid of binder.

10. A stable pharmaceutical composition according to claim 9, wherein the stable pharmaceutical composition is prepared by dry granulation.

. Dated this 3rd October 2018

_______________________
(Patel Dhaval Pinakinbhai)
For Alembic Pharmaceuticals Limited