Novel enteric-coated tablet comprising vortioxetine

FIELD OF THE INVENTION

The present invention relates to a novel enteric-coated tablet comprising vortioxetine as well as the preparation thereof.

BACKGROUND OF THE INVENTION

1 -{2-[(2,4-dimethylphenyl)sulfanyl]phenyl}piperazine and pharmaceutically acceptable acid addition salts thereof, for example 1 -{2-[(2,4-dimethylphenyl)sulfanyl]phenyl}piperazine hydrobromide, also known as vortioxetine hydrobromide represented by the general formula A, are multimodal serotonergic compounds currently in clinical development for major depressive disorder and generalized anxiety disorder.

General formula A

It has been disclosed in the art that said compounds show antagonistic properties at 5-HT3A and 5-HT7 receptors, partial agonistic properties at 5-HTi _B receptors, agonistic properties at 5- HT-iA receptors and potent serotonin reuptake inhibition via inhibition of the serotonin transporter (SERT). Furthermore, it was for example disclosed in WO 2007/144005 A1 that 1 - [2-(2,4-dimethylphenylsulphanyl)phenyl]piperazine exhibits potent activity on SERT, 5-HT ₃ and 5-HT-iA and may as such be useful for the treatment of cognitive impairment, especially in depressed patients.

Recently, it was described in WO 201 1/023194 that administering vortioxetine and pharmaceutically acceptable acid addition salts thereof in a way so that it shall not be released in the stomach lowers the amount of adverse events, and in particular the amount of Gl tract related adverse events. Therein, different pharmaceutical compositions of vortioxetine comprising a pH sensitive coating are disclosed. Furthermore, EP 2564838 A1 describes an enteric tablet comprising vortioxetine derivatives and an enteric coating layer comprising one or more kinds of polymer components. According to the specification, the amount of talc and the ratio between talc and polymer in the enteric coating as well as the presence or absence of some alkali components may influence the acid resistance and disintegration property of the enteric tablets.

Gastro-resistant tablets are delayed-release tablets that are intended to resist the gastric fluid and to release their active substance(s) in the intestinal fluid. They can be prepared by covering tablets with a gastro-resistant coating (enteric-coated tablets). Generally, a suitable dissolution test as described e.g. in the European Pharmacopoeia has to be carried out to demonstrate the appropriate release of the active substance(s). It is known in the art that many parameters may be of significance in determining the rate and extent of dissolution, the bioavailability, and the uniformity of a drug product.

Hence, there is still a need and thus it is an object of the present invention, to provide a composition comprising 1 -{2-[(2,4-dimethylphenyl)sulfanyl]phenyl}piperazine and pharmaceutically acceptable acid addition salts thereof in a composition having an improved gastro-resistance and an enhanced bioavailability. Furthermore, it is an object of the present invention to provide a composition comprising 1-{2-[(2,4- dimethylphenyl)sulfanyl]phenyl}piperazine and pharmaceutically acceptable acid addition salts thereof in a composition having an improved gastro-resistance and an optimal rate and extent of dissolution. Furthermore, it is an object of the present invention to provide a method of obtaining such a composition.

These objects as well as others, which will become apparent from the following description of the present invention, are attained by the subject-matter of the independent claims. Some of the preferred embodiments of the present invention are defined by the subject matter of the dependent claims.

SUMMARY OF THE INVENTION

Various aspects, advantageous features and preferred embodiments of the present invention as summarized in the following items, respectively alone or in combination, contribute to solving the object of the invention.

1 . A pharmaceutical composition in form of a tablet comprising

a tablet core comprising the compound of formula I (1-{2-[(2,4- dimethylphenyl)sulfanyl]phenyl}piperazine, INN: vortioxetine)

formula I

or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient

(API) and at least one pharmaceutically acceptable excipient,

the tablet core being coated with a pH sensitive coating,

wherein said API has a particle size distribution of D90 of 100 μηη or less, or

D90 of 45 μηη or less, measured by laser diffraction.

The pharmaceutical composition according to item 1 , wherein said API has a particle size distribution of D90: 35-45 μηη or less, D90: 25-35 μηη or less, or D90: 15-25 μηη or less.

The pharmaceutical composition according to item 1 or 2, wherein said API dissolves at most 10% after 2 hours in acid environment and at least 75% after 30 min in neutral environment.

The pharmaceutical composition according to item 3, wherein the acid environment is 0.1 N HCI and the neutral environment is 0.05 M Phosphate buffer, pH 6.8.

The pharmaceutical composition according to item 3 or 4, wherein the temperature of the environment is 37.0±0.5°C.

The pharmaceutical composition according to any of the preceding items, wherein the enteric coating comprises one or more of the following:

a pH sensitive polymer, preferably selected from a group consisting of:

polyacrylamides, phthalate derivatives, styrene and maleic acid copolymers, polyacrylic acid derivatives, methacrylic acid copolymers, vinyl acetate and crotonic acid copolymers;

a lubricant; and/or

a plasticizer. The pharmaceutical composition according to any of the preceding items, wherein the enteric coating comprises one or more of the following: poly(methacrylic acid-co-ethyl acrylate), hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate (CAP) polymer, diethyl phthalate, triethylcitrate, talc. The pharmaceutical composition according to any of the preceding items, wherein the API is a hydrobromic acid (HBr) salt of the compound of formula I. The pharmaceutical composition according to any of the preceding items, wherein the API is in form of crystalline material. The pharmaceutical composition according to item 9, wherein the API has an XRPD pattern with characteristic peaks (expressed in 2Θ ± 0,2° 2Θ (CuKa radiation)) at 5.5°, 14.8°, 16.7° and 20.0°. The pharmaceutical composition according to item 9, wherein the API has an XRPD pattern with characteristic peaks (expressed in 2Θ ± 0,2° 2Θ (CuKa radiation)) at 5.5°, 14.8°, 16.7°, 20.0°, 27.6°, 28.1 °, 28.4°, 28.6°, 29.1 °, 30.5° and 34.4°. The pharmaceutical composition according to item 9, wherein the API has an XRPD pattern with reflections (expressed in 2Θ ± 0,2° 2Θ (CuKa radiation)) at 6.89°, 9.73°, 13.78°, and 14.62°. The pharmaceutical composition according to any of the preceding items, wherein the amount of the API corresponds to 1 to 50 mg, preferably to 5 to 25 mg, more preferable to 5, 10, 15, or 20 mg vortioxetine base. The pharmaceutical composition according to any of the preceding items, wherein the tablet core is obtained by direct compression, dry compaction, or wet granulation. The pharmaceutical composition according to any of the preceding items, wherein the at least one excipient in the tablet core is selected from the following excipients (a) to (d), respectively alone or in combination:

(a) a filler selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, mannitol, starch, anhydrous calcium hydrogen phosphate, and lactose, particularly lactose monohydrate or agglomerated lactose, preferably wherein the filler is mannitol and/or microcrystalline cellulose;

(b) a disintegrant selected from the group consisting of carmellose calcium, carboxymethylstarch sodium, croscarmellose sodium, starch, mize starch, corn starch, modified starch, starch derivatives, crospovidone, and low-substituted hydroxypropylcellulose, preferably superdisintegrants selected from the group consisting of sodium starch glycolate, and corn starch;

(c) a binder, preferably a polymer binder selected from the group consisting of hydroxypropylcellulose (HPC), copovidone, methylcellulose (MC), hypromellose (HPMC), povidone (PVP), tragacanth, sodium alginate, gum arabic, starch pregelatinized, gelatin, and cellulosic derivatives, preferably HPC and/or copovidone;

(d) and/or a lubricant selected from the group consisting of stearic acid, magnesium stearate, calcium stearate, zinc stearate, glyceryl behenate, sodium stearyl fumarate, polyethylene glycol, and silicon dioxide, preferably magnesium stearate. The pharmaceutical composition according to any of the preceding items for use in the treatment of a disease selected from mood disorders, major depressive disorder, general anxiety disorder; panic disorder; post-traumatic stress disorder, depression associated with cognitive impairments, Alzheimer's disease or anxiety; depression with residual symptoms; chronic pain; eating disorder and/or abuse. A method of preparing a tablet comprising the compound of formula I (1-{2-[(2,4- dimethylphenyl)sulfanyl]phenyl}piperazine, INN: vortioxetine)

formula I or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API),

the process comprising the steps of: providing said API having a particle size distribution of a D90 of 100 μηι or less, or D90 of 45 μηι or less, measured by laser diffraction;

mixing said provided API with at least one pharmaceutically acceptable excipient and preparing a tablet core thereof;

applying a pH sensitive coating on said tablet core. The method according to item 17, wherein the particle size distribution has a particle size distribution of D90: 35-45 μηη or less, D90: 25-35 μηη or less, or D90: 15-25 μηη or less. The method according to items 17 or 18, wherein the API dissolves at most 10% after 2 hours in acid environment and at least 75% after 30 min in neutral environment. The method according to any of the preceding items, wherein the at least one pharmaceutically acceptable excipient in the tablet core is at least one of the following excipients (a) to (d), respectively alone or in combination:

(a) a filler selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, mannitol, starch, anhydrous calcium hydrogen phosphate, and lactose monohydrate, preferably mannitol and/or microcrystalline cellulose;

(b) a disintegrant selected from the group consisting of carmellose calcium, carboxymethylstarch sodium, croscarmellose sodium, starch, mize starch, corn starch, modified starch, starch derivatives, crospovidone, and low-substituted hydroxypropylcellulose, preferably superdisintegrants selected from the group consisting of sodium starch glycolate, and corn starch;

(c) a binder, preferably a polymer binder selected from the group consisting of hydroxypropylcellulose (HPC), copovidone, methylcellulose (MC), hypromellose (HPMC), povidone (PVP), tragacanth, sodium alginate, gum arabic, starch

pregelatinized, gelatin, and cellulosic derivatives, preferably HPC and/or copovidone;

(d) and/or a lubricant selected from the group consisting of stearic acid, magnesium stearate, calcium stearate, zinc stearate, glyceryl behenate, sodium stearyl fumarate, polyethylene glycol, and silicon dioxide, preferably magnesium stearate. The method according to any of the preceding items, wherein the tablet core is prepared by direct compression, dry compaction or wet granulation. The method according to any of the preceding items, wherein the enteric coating comprises one or more of the following: poly(methacrylic acid-co-ethyl acrylate), hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate (CAP) polymer, diethyl phthalate, triethylcitrate, talc.

23. The method according to any of the preceding items, wherein the API is a

hydrobromic acid (HBr) salt of the compound of formula I.

24. The method according to any of the preceding items, wherein the API is in form of crystalline material.

25. The method according to item 24, wherein the API has an XRPD pattern with

characteristic peaks (expressed in 2Θ ± 0,2° 2Θ (CuKa radiation)) at 5.5°, 14.8°, 16.7° and 20.0°.

26. The method according to item 24, wherein the API has an XRPD pattern with characteristic peaks (expressed in 2Θ ± 0,2° 2Θ (CuKa radiation)) at 5.5°, 14.8°, 16.7°, 20.0°, 27.6°, 28.1 °, 28.4°, 28.6°, 29.1 °, 30.5° and 34.4°.

27. The method according to item 24, wherein the API has an XRPD pattern with reflections (expressed in 2Θ ± 0,2° 2Θ (CuKa radiation)) at 6.89°, 9.73°, 13.78°, and 14.62°.

28. The method according to any of the preceding items, wherein the amount of the API corresponds to 1 to 50 mg, preferably to 5 to 25 mg, more preferable to 5, 10, 15, or 20 mg vortioxetine base.

29. The method according to any of the preceding items for the manufacture of a

medicament for use in the treatment of a disease selected from mood disorders, major depressive disorder, general anxiety disorder; panic disorder; post-traumatic stress disorder, depression associated with cognitive impairments, Alzheimer's disease or anxiety; depression with residual symptoms; chronic pain; eating disorder and/or abuse.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 : Dissolution profile of a tablet according to the invention at pH 6.8 (Example 1 ) Figure 2: Dissolution profile of the API (vortioxetine HBr) at pH 6.8 (Comparative

Example 1 ) DETAILED DESCRIPTION OF THE INVENTION

It is known in the art that many parameters may be of significance in determining the rate and extent of dissolution, the bioavailability, and the uniformity of a drug product. One of such parameters is the particle size of the active pharmaceutical ingredient (API) and the particle size distribution. However, the inventors found that in the case of the hydrobromide salt of vortioxetine, the API itself do not seem to show a significant dependence of the dissolution behavior from the particle size (see Reference Example 1 ). This result seems to confirm the previous findings in the art.

For instance, WO 2007/144005 A1 discloses on page 20 that the beta form of vortioxetine hydrobromide can be used having a particle size distribution of e.g. D98: 650-680 μηη, D98: 370-390 m, D98: 100-125 μηι, or D98: 50-70 μηι. Also the disclosed D50 and D5 values cover a wide range (ranging from 3 m to 250 m for D50, and ranging from 0.5 m to 60 m for D5). Despite of this findings, the problem of providing a composition having an improved gastro-resistance and an optimal rate and extent of dissolution was further investigated by the present inventors.

Surprisingly, the present inventors have discovered that relatively fine particle sizes of the above-defined API critically influence the dissolution rate of an enteric-coated tablet comprising said API . Only a tablet having the API particle size distribution in combination with an enteric coating as defined in the present invention, unexpectedly meets the requirements of the Pharmacopoea Europaea (Ph. Eur., 8 ^th ) regarding gastro-resistance.

Based on these findings, the inventors developed pharmaceutical compositions with an advantageous dissolution profile of vortioxetine hydrobromide that enables controlled release of vortioxetine hydrobromide, thereby allowing an excellent balance between reduced adverse events and release profile of the vortioxetine hydrobromide upon administration to a patient.

The invention is described below in further detail by embodiments, without being limited thereto.

One embodiment of the present invention refers to a pharmaceutical composition in form of a tablet comprising a tablet core comprising the compound vortioxetine or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API) and at least one pharmaceutically acceptable excipient. In this embodiment, the tablet core is coated with a pH sensitive coating and the API has a particle size distribution of D90 of 100 μηη or less, measured by laser diffraction. As used herein, the term "tablet", is defined as the solid unit dosage form of medicament or medicaments with or without suitable diluents. It comprises a mixture of the API and excipients, usually in powder form, pressed or compacted from a powder into a solid dose. The excipients can include diluents, binders or granulating agents, glidants (flow aids) and lubricants to ensure efficient tableting; disintegrants to promote tablet break-up in the digestive tract; sweeteners or flavours to enhance taste; and pigments to make the tablets visually attractive or aid in visual identification of an unknown tablet.

A polymer coating can be applied to the tablet core to make the tablet smoother and easier to swallow, to control the release rate of the active ingredient, to make it more resistant to the environment (extending its shelf life), or to enhance the tablet's appearance. Accordingly, as used herein, the term "enteric coating", often also referred as pH sensitive coating, means a coating including polymers, which are insoluble in acidic medium and contain carboxylic functions that are deprotonated in neutral or basic environment and dissolves by deprotonation and salt formation.

As used herein, the terms "API" or "active pharmaceutical ingredient" refer to the compound vortioxetine (i.e. 1-{2-[(2,4-dimethylphenyl)sulfanyl]phenyl}piperazine) or a pharmaceutically acceptable salt thereof.

Particle sizes were assessed using laser diffraction methods. Laser diffraction is recognized by standards and guidance agencies including ISO and ASTM and is widely used to determine particle size distributions. In conducting the assessment, the sample is passed through a laser beam which results in laser light scattered at a range of angles. Detectors placed at fixed angles measure the intensity of light scattered at that position. A mathematical model (Mie or Fraunhoffer Theory) is then applied to generate a particle size distribution.

In particle size determinations, the median value is defined as the value where half of the population resides above this point, and half resides below this point. For particle size distributions the median is called the D50. The D50 is the size in microns that splits the distribution with half above and half below this diameter. The expression Dv50 or D[v,0.5] is sometimes used for the median of a volume distribution. The mode is the peak of a frequency distribution. A particle distribution may include more than one mode, e.g., where the particles exist as primary particles and agglomerations.

The distribution width may be characterized by citing one, two or three values on the x-axis, typically D10, D50, and/or D90. The D50, the median, has been defined above as the diameter where half of the population lies below this value. Similarly, 90 percent of the distribution lies below the D90, and 10 percent of the population lies below the D10. In one aspect, the API according to the present invention has a particle size distribution of D90: 100 μηι or less. In another aspect, the API according to the present invention has a particle size distribution of D90: 35-45 μηι or less, D90: 25-35 μηι or less, D90: 15-25 μηι or less, or D90: 10-15 μηι or less. In another aspect, the particle size distribution of the API has a D90 of at most 25-35 μηη, a D90 of at most 15-25 μηη, and/or a D90 of at most 10-15 μηη. Alternatively, the particle size distribution of the API has a D90 of 25-35 μηι, a D90 of 15-25 μηι, or a D90 of 10-15 μηη. In still another aspect, the invention provides a solid form of 1 -{2-[(2,4- dimethylphenyl)sulfanyl]phenyl}piperazine, having a D90 value of from about 10 μηη to about 45 μηη.

In other embodiments, the API has a primary particle size distribution characterized by a D90 value of: from about 10 μηη to about 100 μηη; from about 10 μηη to about 90 μηη, from about 10 μηη to about 80 μηη, from about 10 μηη to about 70 μηη, from about 10 μηη to about 60 μηη, from about 10 μηη to about 50 μηη, from about 10 μηη to about 45 μηη, from about 10 μηη to about 40 μηη, from about 10 μηη to about 35 μηη, from about 10 μηη to about 30 μηη, from about 10 μηη to about 25 μηη, from about 10 μηη to about 20 μηη, or from about 10 μηη to about 15 μηη.

In other embodiments, the API has a primary particle size distribution characterized by a D90 value of: from about 10 μηη to about 45 μηη, from about 10 μηη to about 40 μηη, from about 10 μηη to about 35 μηη, from about 10 μηη to about 30 μηη, from about 10 μηη to about 25 μηη, from about 10 μηη to about 20 μηη, or from about 10 μηη to about 15 μηη. In this embodiment, the API can have a primary particle size distribution characterized by a D90 value of: from about 20 μηη to about 45 μηη, from about 20 μηη to about 40 μηη, from about 20 μηη to about 35 μηη, from about 20 μηη to about 30 μηη, or from about 20 μηη to about 25 μηη. Alternatively, the API can have a primary particle size distribution characterized by a D90 value of: from about 30 μηη to about 45 μηη, from about 30 μηη to about 40 μηη, or from about 30 μηη to about 35 μηη. Alternatively, the API can have a primary particle size distribution characterized by a D90 value of: from about 35 μηη to about 45 μηη, or from about 35 μηη to about 40 μηη.

D90 as used herein means that 90% of the particles (based on volume) are smaller than or equal to the indicated size.

The above-mentioned API particles may be obtained by milling as known in the art. For example, particles may be milled in a Retsch Ball Mill with a 35 ml chamber for 10 min at a frequency of 25 Hz.

For the purpose of this invention, particle size distribution is determined as the percent volume at each particle size and can be measured by a laser diffraction method, typically using a Malvern Mastersizer 3000 laser diffraction analyzer with the Mie theory and dry measurement in the context of Aero S in accordance with ISO 13320:2009. In more detail, the following parameters may be used:

Initial weight: 200 mg.

Obscuration: 1 -6 %.

Background time 12 s.

Measurement time: 12 s.

Diffraction method: Mie theory.

Particle refractive index: 1 .58.

Absorption factor: 0.01.

Analysis model: General purpose.

Sensitivity: Enhanced.

Feed rate: 80%.

Feed tray: Standard venture.

Width of sample tray: 1.0 mm.

Disperser pressure: 2 bar.

Sieve: Sieve with one ball

As meant herein, the above-mentioned pharmaceutically acceptable salts of vortioxetine are acid addition salts of acids that are non-toxic. Said salts include salts made from organic acids, such as maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p- aminobenzoic, glutamic, benzenesulfonic, theophylline acetic acids, as well as the 8- halotheophyllines, for example 8-bromotheophylline as described in WO 2007/144005. Preferably, said salts are made from inorganic salts, such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids and salts made from methanesulfonic acid, maleic acid, fumaric acid, meso-tartaric acid, (+)-tartaric acid, (-)-tartaric acid, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphorous acid and nitric acid. In a preferred embodiment, the above-mentioned pharmaceutically acceptable salt is vortioxetine hydrobromide.

Furthermore, the above-mentioned API may be present in a crystalline form. In a preferred embodiment, the API is vortioxetine hydrobromide having an XRPD pattern with characteristic peaks (expressed in 2Θ ± 0,2° 2Θ (CuKa radiation)) at 5.5°, 14.8°, 16.7° and 20.0°, and more preferably an XRPD pattern with characteristic peaks (expressed in 2Θ ± 0,2° 2Θ (CuKa radiation)) at 5.5°, 14.8°, 16.7°, 20.0°, 27.6°, 28.1 °, 28.4°, 28.6°, 29.1 °, 30.5° and 34.4°. Such a crystalline form and a method for its production is disclosed in WO 2014/044721 .

In another preferred embodiment, the API is crystalline vortioxetine hydrobromide having an XRPD pattern with reflections (expressed in 2Θ ± 0,2° 2Θ (CuKa radiation)) at 6.89°, 9.73°, 13.78°, and 14.62°. Such a crystalline form is disclosed in the Table on page 6 and in Figure 3 of WO 2007/144005 (see also Example 4d). A method for its production is disclosed in Example 4c of WO 2007/144005.

In another embodiment, the API is crystalline vortioxetine hydrobromide having an XRPD pattern as shown in any of Figures 1-17 of WO 2007/144005, in particular Figures 2, 3, 4 or 5. According to page 3 of WO 2007/144005, Figures 2-5 show the XRPD of "alpha form" of vortioxetine hydrobromide, the XRPD of "beta form" of vortioxetine hydrobromide, the XRPD of "gamma form" of vortioxetine hydrobromide and the XRPD of "hemi hydrate" of vortioxetine hydrobromide.

Vortioxetine, particularly vortioxetine hydrobromide as well as it's crystalline forms mentioned above may be prepared as known in the art and described elsewhere, for example in WO 2014/044721 A1 and WO 2007/144005. Alternatively, the compound may be prepared as disclosed in e.g. WO 2014/161976 or WO 2014/191548.

A tablet according to the invention may comprise the API in an amount corresponding to 0.25 to 50 mg vortioxetine base, preferably corresponding to 1 to 50 mg vortioxetine base, more preferable to 1 to 25 mg vortioxetine base. In one embodiment, the tablet comprises the API corresponding to 5 mg vortioxetine base. Alternatively, the tablet comprises 10, 15, or 20 mg.

In addition to the API, a tablet according to the invention is further comprising at least one pharmaceutically acceptable excipient in the tablet core. Said at least one pharmaceutically acceptable excipient may be for example a filler, a disintegrant, a polymer and/or a lubricant. In a preferred embodiment, the tablet core comprises at least the API, a filler, a disintegrant, a granulation polymer or binder and a lubricant.

The filler, when preferably contained in the tablet according to the present invention, is preferably selected from cellulose fillers such as microcrystalline cellulose, e.g. Avicel® such as Avicel PH 102, and silicified microcrystalline cellulose (e.g. Prosolv®), and non-cellulose fillers such as polyols, for instance isomalt (e.g. GalenlQ®), mannitol (e.g. Pearlitol®), preferably Pearlitol 200SD, lactose, such as lactose monohydrate, agglomerated lactose such as Tablettose 70 or Tablettose 80, or xylitol, or polymer filler such as starch (e.g. starch 1500) or anhydrous calcium hydrogen phosphate or lactose monohydrate. The selected filler preferably has plastic deformation properties under compression. Microcrystalline cellulose and Pearlitol 200SD are particularly preferred.

The disintegrant, when preferably contained in the tablet according to the present invention, is preferably selected from the group consisting of carmellose calcium, carboxymethylstarch sodium, croscarmellose sodium (cellulose carboxymethylether sodium salt, cross-linked), starch, such as mize starch or corn starch, modified starch such as pregelatinized starch, starch derivatives such as sodium starch glycolate, cross-linked polyvinylpyrrolidone (crospovidone), and low-substituted hydroxypropylcellulose. Particularly preferable disintegrants are superdisintegrants and are selected from the group consisting of sodium starch glycolate, croscarmellose sodium and crospovidone, in particular is croscarmellose sodium.

The binder, when preferably contained in the tablet according to the present invention, is preferably selected from matrix type polymer binder and/or a granulation polymer binder, specifically cellulose derivative-type polymer binder such as hydroxypropyl cellulose (HPC, e.g. Klucel®), hydroxypropylmethylcellulose (e.g. Methocel®), copovidone, methylcellulose (MC), hypromellose (HPMC), povidone, tragacanth, sodium alginate, gum arabic, gelatin, and starch pregelatinized. Preferably the binder is cellulosic derivatives, more preferably hydroxypropylcellulose. Binding agents is generally used to improve adhesion of powder particles during wet granulation. The selected binder preferably has plastic deformation properties under compression. For that purpose, excipients from the group of cellulose derivatives can favourably be utilized and are preferred, particularly Klucel EF hydroxypropyl cellulose.

The lubricant, when preferably contained in the tablet according to the present invention, is preferably selected from the group consisting of colloidal silicon dioxide such as Aerosil®, talc, stearic acid, magnesium stearate, calcium stearate, zinc stearate, glyceryl behenate, sodium stearyl fumarate, polyethylene glycol, and silicon dioxide; more preferably the lubricant is magnesium stearate.

According to one embodiment of the present invention, the tablet core comprises the above- mentioned API, a filler, a disintegrant, a granulation polymer (binder) and a lubricant.

Preferably, the above-defined excipients are comprised in the tablet core in the following amounts (% by weight): API: 2-20%

Filler: 60-90%

Disintegrant 2-10%

Granulation polymer: 0-10%

Lubricant: 0.5-2.5%

The above-mentioned tablet core may be prepared by any method known in the art. In one embodiment, the tablet core is prepared by direct compression. Alternatively, the tablet core is prepared by dry compaction. Alternatively, the tablet core is prepared by wet granulation.

Then, an enteric coating is applied to the tablet core. As long as the condition about the API size characteristic is observed, any pH sensitive coating known in the art can be used for a tablet according to the invention. For example a coating is suitable, which is comprising a pH sensitive polymer, wherein the pH sensitive polymer is preferably selected from a group consisting of polyacrylamides, phthalate derivatives, styrene and maleic acid copolymers, polyacrylic acid derivatives, methacrylic acid copolymers, vinyl acetate and crotonic acid copolymers, more preferably poly(methacrylic acid-co-ethyl acrylate), hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate phthalate (CAP) polymer, preferably in an aqueous dispersion comprising 30 percent by weight CAP, diethyl phthalate, triethylcitrate. In one further preferred embodiment, the coating comprises HPMCAS-MG, triethylcitrate and talc. In another further preferred embodiment, the coating comprises poly(methacrylic acid-co-ethyl acrylate) 1 :1 , also known as EUDRAGIT® L 30 D- 55, as an aqueous dispersion of 30%, triethylcitrate and talc. In another further preferred embodiment, the coating comprises cellulose acetate phthalate (CAP) polymer, also known as Aquacoat® CPD used as an 30% aqueous dispersion of CAP, and diethyl phthalate.

The pH sensitive coating may be applied by any method known in the art. Typically, a film coating step is applied.

Moreover, an enteric-coated tablet of the present invention may comprise further excipients, such as diluents, sweeteners, buffering agents, glidants, flowing agents, flavouring agents, preservatives, surfactants, wetting agents, and thickeners.

In a preferred embodiment, the tablet core comprises the following excipients: mannitol, microcrystalline cellulose, hydroxypropylcellulose, sodium starch glycolate (type A), and magnesium stearate.

Vortioxetine hydrobromide provided in a pharmaceutical composition according to the invention has an excellent balance between adverse events and release profile. The pharmaceutical composition as described above allows a controlled dissolution profile of vortioxetine hydrobromide as defined herein. In consequence, only small amounts of vortioxetine hydrobromide are released in the stomach passage of a human patient where vortioxetine hydrobromide can lead to nausea. The major amount of the vortioxetine hydrobromide is released in the intestine.

The term "release", as used herein, refers to the release of the pharmaceutically active ingredient, i.e. vortioxetine hydrobromide, from a dosage form comprising the pharmaceutical composition after exposing same to conditions whereupon the pharmaceutically active ingredient is released from the dosage form. The term "release rate" or "release profile" refers to the (percentage) amount released per time unit from the dosage form comprising the pharmaceutical composition. For the purpose of the invention of this invention, the in-vivo release profile will be assumed as corresponding to the in-vitro dissolution profile as explained below and will be measured as explained below and in the examples by means of the (in-vitro) dissolution rate. Determining the dissolution profile of the pharmaceutical composition of the present invention can be done e.g. by using the USP Dissolution Apparatus 2 (Paddle). With respect to details of the process it is referred to the dissolution tests described in the US Pharmacopeial Convention <71 1 > and/or the European Pharmacopeia (2.9.3.).

Determining the dissolution profile of the pharmaceutical composition of the present invention can be done as follows: The pharmaceutical composition is placed in 900 ml. of 0.1 N hydrochloric acid, stirred for 2 hours at 50 rpm to 75 rpm at a temperature of 37±0.5 °C. The dissolution profile is then determined e.g. by taking aliquots at defined time points (e.g. 20 min, 40 min, 60 min, 80 min, 100 min, and 120 min), followed by measuring the vortioxetine hydrobromide amount contained in the aliquots in a suitable assay. The pharmaceutical composition is then placed in 900 ml. of 0.05M Phosphate buffer pH 6,8, stirred for 1 hour at 50 rpm to 75 rpm at a temperature of 37±0.5 °C. The dissolution profile is then determined e.g. by taking aliquots at defined time points (e.g. 10, min, 20 min, 30 min, 40 min, 50 min, and 60 min), followed by measuring the vortioxetine hydrobromide amount contained in the aliquots in a suitable assay. Similarly, the dissolution profile of the API can be determined (in 900 ml_ of 0.05M Phosphate buffer pH 6,8).

A coated tablet according to the invention preferably exhibits the following in vitro dissolution characteristics: The above-mentioned API dissolves at most 10% after 2 hours in acid environment and at least 75% after 30 min in neutral environment. Preferably, the above- mentioned API dissolves at most 5 -10 % after 2 hours in acid environment and at least 75 - 80 % after 30 min in neutral environment. The above-mentioned acid environment shall reflect the gastric pH, whereas the above- mentioned neutral environment shall reflect the intestinal pH. Preferably, the acid environment of an aqueous medium with a pH of up to pH 2 is used as a reference for the acid environment. More preferably, the reference acid environment is 0.1 N HCI. Further preferred, the neutral environment is of an aqueous medium with a pH of 6 to 8 is used as a reference for the neutral environment. More preferably, the reference neutral environment is represented by 0.05 M Phosphate buffer, pH 6.8.

The dissolution rate may be tested using the following criteria corresponding to a delayed- release dosage form in accordance with the Ph. Eur. (8 ^th ), 2.9.3: at level Ai , no individual of 6 tablets exceeds 10% dissolved API in 2 hours at the acid stage, i.e. 0.1 M HCI. Alternatively, at level A2, the average value of 12 tablets is not more than 10 % dissolved API, and no individual unit is greater than 25 % dissolved. Alternatively, at level A3, the average value of 12 tablets is not more than 10 % dissolved API, and no individual unit is greater than 25 % dissolved. At the buffer stage, i.e. Phosphate buffer solution, pH 6.8 following the acid stage, the requirements are met if a value Q of at least 75 % is dissolved, wherein Q corresponds to the total amount of the active substance dissolved in both the acid and the buffer stages.

The dissolution rate may be tested at a temperature of 37±0.5°C. Alternatively, the dissolution rate may be tested at room temperature. The dissolution rate may be tested by stirring between about 50 rpm and about 75 rpm, preferably at about 50 rpm or about 75 rpm.

Unless otherwise noted or obvious in the circumstances, percentage terms used herein refer to weight/weight (w/w) percentages. Unless otherwise noted or obvious in the circumstances, the term "about" means ± 10% (preferably ± 5%) of the indicated value.

EXAMPLES

Example 1

For preparing a tablet according to the invention (Formulation A), the following ingredients and amounts were used (Table 1 ). A tablet according to Formulation B not according to the invention was prepared and used for comparative purposes.

Table 1 :

^* Dry substance. Used as 30% aqueous dispersion of Methacrylic Acid - Ethyl Acrylate Copolymer. Tablet core:

For preparing the tablet core, vortioxetin HBr, Mannitol, MCC, Primojel and Klucel were sieved via 1.0mm. The mixture was granulated with water (appr. 50g/min). The wet granules were sieved via 2.0 mm and dried in fluid bed. After drying, the granules were again sieved via

I .0mm.

Mg stearate was sieved via 0.5mm and mixed with the dried granules for 5 min.

The blend was compressed on a rotary press (8mm round) with a main compression force of

I I .5-12kN resulting in a tablet hardness of 70-87 N.

Coating:

For preparing the coating, triethylcitrate was dissolved in water. Then, talc was homogeneously dispersed in water. Afterwards, triethylcitrate solution and talc suspension were combined and Eudragit dispersion (sieved via 0.1 mm) was added. Dispersion was stirred 1 h before start of coating and further continuously stirred during the whole coating process.

Tablet cores were coated with the coating dispersion in a GLATT Minicoater 0,8 liter volume. After coating tablets were tempered for 2h at 40°C in an oven.

Check of qastro resistance:

Paddle, 75rpm, 900ml, 2h 0.1 N HCI, afterwards change to 0.05M Phosphate buffer pH 6,8.

Figure 1 summarizes the dissolution rate of Formulation A compared to Formulation B at pH 6.8

Table 2:

Time (min) % release

Formulation A Formulation B

0 0 0 0.1 N HCI

120 1 2

0 0 0 pH 6.8

5 8 6

10 64 20

15 73 28

30 81 41

45 82 50

60 83 54 As can be seen from Figure 1 and Table 2 above, the release of the tablet is dependent from the API particle size. Only Formulation A (fine particle size) fulfills the requirements of Ph. Eur. regarding gastro-resistance, i.e. max 10% after 2h in 0.1 N HCI; min 75% (Q) after 30min in pH 6,8.

Example 2

For preparing a second tablet according to the invention (Formulation C), the following ingredients and amounts are used (Table 3). A tablet according to Formulation D not according to the invention is intended for comparative purposes.

Table 3:

Tablet core:

For preparing the tablet core, vortioxetin HBr, Mannitol, MCC, Primojel and Klucel are sieved via 1 .0mm. The mixture is granulated with water (appr. 50g/min). The wet granules are sieved via 2.0mm and dried in fluid bed. After drying the granules are again sieved via 1.0mm. Mg stearate is sieved via 0.5mm and mixed with the dried granules for 5min.

The blend is compressed on a rotary press (8mm round; main compression force 1 1.5-12kN; tablet hardness 70-87 N).

Coating:

Triethylcitrate is dissolved in a mixture of Ethanol/water (ratio 7/3). Hydroxypropylmethylcellulose acetate succinate MG is slowly added to this solution and stirred until dissolved. Afterwards talc is suspended while stirring. Dispersion is stirred 1 h before start of coating and further continuously stirred during the whole coating process.

Tablet cores are coated with the coating dispersion in a GLATT Minicoater 0,8 liter volume. Example 3

For preparing a third tablet according to the invention (Formulation E), the following ingredients and amounts are used (Table 4). A tablet according to Formulation F not according to the invention is intended for comparative purposes.

Table 4:

Formulation F

Ingredient Formulation E

[mg]

[mg]

Vortioxetin HBr 6.36 6.36

(amount corresponding to

5mg Vortioxetine base) D(90) 15/jm D(90) 155/jm

Anhydrous calcium

59.64 59.64

hydrogen phosphate

Corn starch 30.00 30.00

Copovidone 4.50 4.50

Microcrystalline cellulose 37.50 37.50

Sodium starch glycolate

4.50 4.50

(Primojel)

Talc 6.00 6.00

Mg stearate 1.50 1.50

150.0 150.0 Aquacoat CPD 12.09 12.09

Diethyl phthalate 2.91 2.91

165.00 165.00

^* Dry substance. Used as 30% aqueous dispersion of cellulose acetate phthalate. Tablet core:

Vortioxetin HBr, Calcium hydrogen phosphate, Corn starch and Microcrystalline Cellulose are sieved via 1 .0mm and mixed. The mixture is granulated with a solution of Copovidone in water (appr. 50g/min). The wet granules are sieved via 2.0mm and dried in fluid bed. After drying the granules are again sieved via 1.0mm.

Talc and Sodium starch glycolate are added to the granules and mixed for 10min.

Finally Mg stearate is sieved via 0.5mm, added and mixed with the powder mixture for 5min.

The blend is compressed on a rotary press (8mm round; main compression force 8-12kN; tablet hardness 50-70 N).

Coating:

Aquacoat CPD is mixed and Diethyl phthalate is slowly added while mixing. The dispersion is mixed for 30min. Afterwards water is added and mixed for further 10min. The dispersion is stirred continuously during the whole coating process.

Tablet cores are coated with the coating dispersion in a GLATT Minicoater 0,8 liter volume.

Reference example 1

The dissolution profiles of vortioxetine HBr API having particule size distributions of D90 of 12 μηη, 43 μηη and 580 μηη are depicted in Figure 2. The release of vortioxetine hydrobromide in 0.05 M Phosphate buffer, pH 6.8 was independent from the particle size distribution (Paddle, pH 6.8 / 50 rpm / 900ml). Hence, it was very surprising that a clear dependence was found with the finished dosage form.