EP4093402A1 - Crystalline form c of vortioxetine hydrobromide - Google Patents

Crystalline form c of vortioxetine hydrobromide

Info

Publication number
EP4093402A1
EP4093402A1 EP21744455.3A EP21744455A EP4093402A1 EP 4093402 A1 EP4093402 A1 EP 4093402A1 EP 21744455 A EP21744455 A EP 21744455A EP 4093402 A1 EP4093402 A1 EP 4093402A1
Authority
EP
European Patent Office
Prior art keywords
crystalline form
vortioxetine hydrobromide
less
composition
vortioxetine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP21744455.3A
Other languages
German (de)
French (fr)
Other versions
EP4093402A4 (en
Inventor
Fatih Sunel
Onur Mutlu
Yavuz Dedeoglu
Muge ULUSOY BOZYEL
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanovel Ilac Sanayi ve Ticaret AS
Original Assignee
Sanovel Ilac Sanayi ve Ticaret AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sanovel Ilac Sanayi ve Ticaret AS filed Critical Sanovel Ilac Sanayi ve Ticaret AS
Publication of EP4093402A1 publication Critical patent/EP4093402A1/en
Publication of EP4093402A4 publication Critical patent/EP4093402A4/en
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • the present invention relates to crystalline form C of vortioxetine hydrobromide for use in the treatment of major depressive disorder (MDD). Furthermore, the invention provides a composition comprising crystalline form C of vortioxetine hydrobromide and processes for the preparation of compositions comprising the form C.
  • MDD major depressive disorder
  • MDD Major depressive disorder
  • a disabling, severe mental disorder characterized by episodes of all-encompassing low mood accompanied by low self- esteem and loss of interest or pleasure in normally enjoyable activities. The illness tends to be chronic and repeated episodes are common.
  • Other symptoms of MDD may include irritability or frustration, sleep disturbances, tiredness and lack of energy, changes in appetite, anxiety, agitation, restlessness, feelings of worthlessness or guilt, trouble thinking and concentrating, and unexplained physical problems, such as back pain or headaches.
  • the exact causes of MDD are unknown, it is believed that a variety of factors may be involved, such as brain chemistry and physical brain differences, hormones, inherited traits and life events.
  • Vortioxetine is a multimodal serotonergic compound intended to be used in the treatment of major depressive disorder and generalized anxiety disorder and it has been shown to be an antagonist on the 5-HT3, 5-HT7 and 5-HT1 D receptors, an agonist at the 5-HT1 A receptor and a partial agonist at the 5-HT1 B receptor, and an inhibitor of the serotonin transporter (SERT).
  • SERT serotonin transporter
  • the chemical name of vortioxetine is 1-[2-(2,4-dimethylphenyl) sulfanylphenyl] piperazine. Its chemical structure is illustrated with formula I given below.
  • Vortioxetine hydrobromide is indicated for the treatment of major depressive disorder (MDD). It is a serotonin (5-HT) reuptake inhibitor, which is considered as its mechanism of action for the treatment of MDD.
  • MDD major depressive disorder
  • 5-HT serotonin
  • BRINTELLIX which contains the beta (b) polymorph of Vortioxetine hydrobromide, an antidepressant.
  • Vortioxetine free base is disclosed in WO 2003/029232 A1.
  • WO 2007/144005 A1 discloses crystalline vortioxetine free base, a variety of crystalline polymorphs and pseudopolymorphs of vortioxetine hydrobromide, including a hemihydrate and an ethyl acetate solvate thereof, crystalline vortioxetine hydrochloride and a monohydrate thereof, and crystalline forms of vortioxetine mesylate, hydrogenfumarate, hydrogenmaleate, mesohydrogentartrate, L-(+)-hydrogentartrate, D-(-)-hydrogentartrate, hydrogen sulphate, dihydrogenphosphate and nitrate.
  • WO2014177491(A) describes a pharmaceutical composition of amorphous vortioxetine hydrobromide and an adsorbent and the process to produce the same.
  • MDD major depressive disorder
  • the main object of the present invention is to provide crystalline form C of Vortioxetine hydrobromide for use in the treatment of major depressive disorder (MDD) and so, providing rapid and effective treatment and bioavailability and bringing additional advantages over the relevant prior art.
  • MDD major depressive disorder
  • Another object of the present invention is to provide a composition comprising crystalline form C of Vortioxetine hydrobromide for use in the treatment of major depressive disorder (MDD) having desired stability and dissolution profile.
  • Vortioxetine hydrobromide is slightly soluble in water; at ambient temperature solubility is equivalent to approximately 1.3 mg base/mL, pH being 5.5 in the saturated solution. The solubility of crystalline polymorph forms is higher compared to the solubility of amorphous forms.
  • MDD major depressive disorder
  • the XRD pattern match with 2Q values at 8.3, 8.8, 16.1 and 19.0 ( ⁇ 0.2Q) corresponds to crystalline form-C of Vortioxetine Hydrobromide.
  • the crystalline form-C of vortioxetine hydrobromide is for use in the treatment of major depressive disorder (MDD).
  • the recommended normal use dose for the crystalline form-C of vortioxetine hydrobromide is 10 mg once daily for adults younger than 65 years. According to your response to your treatment of major depressive disorder (MDD), your doctor may increase this dose to a maximum of 20 mg per day, or at least 5 mg per day. The initial dose for patients 65 years and older is 5 mg taken once a day.
  • MDD major depressive disorder
  • particle size means the cumulative volume size distrubition as tested by any conventionally accepted method such as the laser diffraction method (i.e. malvern analysis).
  • d (0.1) means, the size at which 10% by volume of the particles are finer and d (0.5) means the size at which 50% by volume of the particles are finer and d (0.9) means the size at which %90 by volume of the particles are finer.
  • Laser diffraction measures particle size distributions by measuring the angular variation in intensity of light scattered as a laser beam passes through a dispersed particulate sample. Large particles scatter light at small angles relative to the laser beam and small particles scatter light at large angles, as illustrated below. The angular scattering intensity data is then analyzed to calculate the size of the particles responsible for creating the scattering. The particle size is reported as a volume equivalent sphere diameter.
  • the value of particle size of crystalline form-C of vortioxetine hydrobromide for use in the treatment of major depressive disorder (MDD) is important that it helps to provide dissolution rate, and therefore a high bioavailability and a long-term stability.
  • crystalline form-C of vortioxetine hydrobromide has a d (0.1) particle size which is less than 100 pm, less than 90 pm, less than 80 pm, less than 70 pm, less than 60 pm, less than 50 pm, less than 40 pm, less than 30 pm, less than 25 pm, less than 20 pm, less than 10 pm.
  • crystalline form-C of vortioxetine hydrobromide has a d (0.5) particle size which is less than 200 pm, less than 180 pm, less than 160 pm, less than 140 pm, less than 120 pm, less than 100 pm, less than 80 pm, less than 70 pm, less than 60 pm, less than 50 pm, less than 40 pm, less than 30 pm, less than 25 pm, less than 20 pm.
  • crystalline form-C of vortioxetine hydrobromide has a d (0.9) particle size which is less than 250 pm, less than 240 pm, less than 230 pm, less than 220 pm, less than 210 pm, less than 200 pm, less than 180 pm, less than 160 pm, less than 140 pm, less than 120 pm, less than 100 pm, less than 80 pm, less than 70 pm, less than 60 pm, less than 50 pm, less than 40 pm, less than 30 pm, less than 25 pm, less than 20 pm.
  • crystalline form-C of vortioxetine hydrobromide has a d (0.1) particle size which between 100 pm to 5 pm, a d (0.5) particle size which between 200 pm to 10 pm, a d (0.9) particle size which between 250 pm to 10 pm.
  • the composition comprising crystalline form C of vortioxetine hydrobromide for use in the treatment of major depressive disorder (MDD) is formulated a solid oral dosage form or injectable form.
  • composition of the present invention is provided as solid oral dosage form.
  • Solid oral dosage forms include, but are not limited to tablets, hard or soft capsules, caplets, lozenges, pills, mini-tablets, tablets, pellets, beads, granules (e.g. packaged in sachets).
  • Compositions for solid oral dosage form are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions.
  • the tablet is in the form of coated tablet, film- coated tablet, trilayer tablet, bilayer tablet, multilayer tablet, orally disintegrating tablet, mini tablet, pellet, buccal tablet, sublingual tablet, effervescent tablet, immediate release tablet, modified release tablet.
  • the solid oral dosage composition of the present invention comprises at least one pharmaceutically acceptable excipient which is selected from the group comprising fillers, binders, disintegrants, lubricants, glidants or mixtures thereof in order to provide the desired dissolution profile.
  • Suitable fillers are selected from the group comprising microcrystalline cellulose, mannitol, lactose monohydrate, starch, dibasic calcium phosphate, tribasic calcium phosphate, trehalose, isomalt, sodium carbonate, sodium bicarbonate, calcium carbonate, carboxymethyl cellulose, polydextrose, polyethylene oxide, hydroxypropyl methyl cellulose, methyl cellulose, polyethylene glycol or mixtures thereof.
  • the amount of filler is between 30.0% and 95.0% by weight of the total composition.
  • the filler is microcrystalline cellulose or mannitol or mixtures thereof.
  • Suitable binders are selected from the group comprising hydroxypropyl cellulose, polyvinylpyrrolidone, sugars, alginates, carbomers, carboxymethylcellulose sodium, cellulose acetate phthalate, chitosan, copovidone, pregelatinized starch, starch mucilage, acacia mucilage, dextrates, dextrin, dextrose, ethylcellulose, glyceryl behenate, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl starch, hypromellose, magnesium aluminum silicate, maltodextrin, maltose, methylcellulose, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethacrylates, aluminia hydroxide, stearic acid, sucrose, bentonite, cetostearyl alcohol, polyoxyethilene-alkyl ethers, pullulan or mixtures thereof.
  • the amount of binder is between 0.1% and 10.0% by weight of the total composition.
  • the binder is hydroxypropyl cellulose.
  • Suitable disintegrants are selected from the group comprising sodium starch glycolate, crospovidone, cross-linked carboxymethyl cellulose (croscarmellose sodium), pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, polyacryline potassium, sodium alginate, alginates, ion- exchange resins, magnesium aluminium silica, poloxamer, sodium glycine carbonate or mixtures thereof. According to one embodiment of the present invention, the amount of disintegrants is between 0.1% and 10.0% by weight of the total composition.
  • the disintegrants is sodium starch glycolate.
  • Suitable lubricants are selected from the group comprising magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, glyseryl palmito sulphate, sodium stearyl fumarate, sodium lauryl sulphate or mixtures thereof.
  • the amount of the lubricant is between 0.1% and 5.0% by weight of the total composition.
  • the lubricant is magnesium stearate.
  • Suitable glidants are selected from the group comprising colloidal silicon dioxide, talc, aluminium silicate, colloidal silica, calcium silicate, magnesium silicate, magnesium oxide, starch or mixtures thereof.
  • the amount of the glidant is between 0.1% and 5.0% by weight of the total composition.
  • the glidant is colloidal silicon dioxide.
  • the composition comprising crystalline form C of vortioxetine hydrobromide for use in the treatment of major depressive disorder (MDD) is formulated an injectable form.
  • injectable form is in the form of intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection, and infusion.
  • the injectable form comprises at least one pharmaceutically acceptable excipient selected from preservatives, surfactants, solvents or mixtures thereof.
  • composition of the present invention can be prepared, using standard techniques and manufacturing processes well known in the art, such as direct compression, wet or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion, spheronization, slugging, spray drying and solvent evaporation.
  • Example 1 A solid pharmaceutical comprising crystalline form C of vortioxetine hydrobromide
  • Example 2 A solid pharmaceutical comprising crystalline form C of vortioxetine hydrobromide
  • Example 3 A film tablet comprising crystalline form C of vortioxetine hydrobromide processed by wet granulation
  • a process for preparing the film tablet comprising crystalline form C of vortioxetine hydrobromide in example 3 comprises the following steps: a) Mixing mannitol 60 and microcrystalline cellulose, crystalline form C of vortioxetine hydrobromide, hydroxypropyl cellulose SSL, sodium starch glycolate, b) Granulating the mixture with water-ethanol mixture, c) Drying the mixture until the humidity is less than 2.0%, then sieving the mixture d) Adding the remaining part of mannitol 60, the remaining part of sodium starch glycolate and colloidal silicon dioxide and then mixing, e) Adding magnesium stearate and then mixing, f) Then, pressing to form tablet and coating.

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Abstract

The present invention relates to crystalline form C of vortioxetine hydrobromide for use in the treatment of major depressive disorder (MDD). Furthermore, the invention provides a composition comprising crystalline form C of vortioxetine hydrobromide and processes for the preparation of compositions comprising the form C.

Description

CRYSTALLINE FORM C OF VORTIOXETINE HYDROBROMIDE
Field of the Invention
The present invention relates to crystalline form C of vortioxetine hydrobromide for use in the treatment of major depressive disorder (MDD). Furthermore, the invention provides a composition comprising crystalline form C of vortioxetine hydrobromide and processes for the preparation of compositions comprising the form C.
Background of the Invention
Major depressive disorder (MDD) is a disabling, severe mental disorder characterized by episodes of all-encompassing low mood accompanied by low self- esteem and loss of interest or pleasure in normally enjoyable activities. The illness tends to be chronic and repeated episodes are common. Other symptoms of MDD may include irritability or frustration, sleep disturbances, tiredness and lack of energy, changes in appetite, anxiety, agitation, restlessness, feelings of worthlessness or guilt, trouble thinking and concentrating, and unexplained physical problems, such as back pain or headaches. Although the exact causes of MDD are unknown, it is believed that a variety of factors may be involved, such as brain chemistry and physical brain differences, hormones, inherited traits and life events.
Vortioxetine is a multimodal serotonergic compound intended to be used in the treatment of major depressive disorder and generalized anxiety disorder and it has been shown to be an antagonist on the 5-HT3, 5-HT7 and 5-HT1 D receptors, an agonist at the 5-HT1 A receptor and a partial agonist at the 5-HT1 B receptor, and an inhibitor of the serotonin transporter (SERT). The chemical name of vortioxetine is 1-[2-(2,4-dimethylphenyl) sulfanylphenyl] piperazine. Its chemical structure is illustrated with formula I given below.
Formula I: Vortioxetine Vortioxetine hydrobromide is indicated for the treatment of major depressive disorder (MDD). It is a serotonin (5-HT) reuptake inhibitor, which is considered as its mechanism of action for the treatment of MDD.
It is available in the market as brand name of BRINTELLIX which contains the beta (b) polymorph of Vortioxetine hydrobromide, an antidepressant.
Vortioxetine free base is disclosed in WO 2003/029232 A1.
WO 2007/144005 A1 discloses crystalline vortioxetine free base, a variety of crystalline polymorphs and pseudopolymorphs of vortioxetine hydrobromide, including a hemihydrate and an ethyl acetate solvate thereof, crystalline vortioxetine hydrochloride and a monohydrate thereof, and crystalline forms of vortioxetine mesylate, hydrogenfumarate, hydrogenmaleate, mesohydrogentartrate, L-(+)-hydrogentartrate, D-(-)-hydrogentartrate, hydrogen sulphate, dihydrogenphosphate and nitrate.
WO2014177491(A) describes a pharmaceutical composition of amorphous vortioxetine hydrobromide and an adsorbent and the process to produce the same.
There still remains a need in the art to provide an improved rapid and effective the treatment of major depressive disorder (MDD) using a crystalline form of vortioxetine hydrobromide having bioavailability and a long-term stability.
When crystalline form C of vortioxetine hydrobromide is used for use in the treatment of major depressive disorder (MDD), it has been unexpectedly found that the rapid and effective treatment and bioavailability of vortioxetine hydrobromide is provided.
Detailed Description of the Invention
The main object of the present invention is to provide crystalline form C of Vortioxetine hydrobromide for use in the treatment of major depressive disorder (MDD) and so, providing rapid and effective treatment and bioavailability and bringing additional advantages over the relevant prior art.
Another object of the present invention is to provide a composition comprising crystalline form C of Vortioxetine hydrobromide for use in the treatment of major depressive disorder (MDD) having desired stability and dissolution profile. Vortioxetine hydrobromide is slightly soluble in water; at ambient temperature solubility is equivalent to approximately 1.3 mg base/mL, pH being 5.5 in the saturated solution. The solubility of crystalline polymorph forms is higher compared to the solubility of amorphous forms. Surprisingly, it has been found that using crystalline form C of vortioxetine hydrobromide provides improved stability and rapid and effective treatment for use in the treatment of major depressive disorder (MDD).
According to one embodiment of the present invention, the XRD pattern match with 2Q values at 8.3, 8.8, 16.1 and 19.0 (± 0.2Q) corresponds to crystalline form-C of Vortioxetine Hydrobromide. The crystalline form-C of vortioxetine hydrobromide is for use in the treatment of major depressive disorder (MDD).
The recommended normal use dose for the crystalline form-C of vortioxetine hydrobromide is 10 mg once daily for adults younger than 65 years. According to your response to your treatment of major depressive disorder (MDD), your doctor may increase this dose to a maximum of 20 mg per day, or at least 5 mg per day. The initial dose for patients 65 years and older is 5 mg taken once a day.
As used here in, ‘particle size’ means the cumulative volume size distrubition as tested by any conventionally accepted method such as the laser diffraction method (i.e. malvern analysis). The term d (0.1) means, the size at which 10% by volume of the particles are finer and d (0.5) means the size at which 50% by volume of the particles are finer and d (0.9) means the size at which %90 by volume of the particles are finer.
Laser diffraction measures particle size distributions by measuring the angular variation in intensity of light scattered as a laser beam passes through a dispersed particulate sample. Large particles scatter light at small angles relative to the laser beam and small particles scatter light at large angles, as illustrated below. The angular scattering intensity data is then analyzed to calculate the size of the particles responsible for creating the scattering. The particle size is reported as a volume equivalent sphere diameter.
According to one embodiment of the present invention, the value of particle size of crystalline form-C of vortioxetine hydrobromide for use in the treatment of major depressive disorder (MDD) is important that it helps to provide dissolution rate, and therefore a high bioavailability and a long-term stability.
According to one embodiment of the present invention, crystalline form-C of vortioxetine hydrobromide has a d (0.1) particle size which is less than 100 pm, less than 90 pm, less than 80 pm, less than 70 pm, less than 60 pm, less than 50 pm, less than 40 pm, less than 30 pm, less than 25 pm, less than 20 pm, less than 10 pm.
According to another embodiment of the present invention, crystalline form-C of vortioxetine hydrobromide has a d (0.5) particle size which is less than 200 pm, less than 180 pm, less than 160 pm, less than 140 pm, less than 120 pm, less than 100 pm, less than 80 pm, less than 70 pm, less than 60 pm, less than 50 pm, less than 40 pm, less than 30 pm, less than 25 pm, less than 20 pm.
According to another embodiment of the present invention, crystalline form-C of vortioxetine hydrobromide has a d (0.9) particle size which is less than 250 pm, less than 240 pm, less than 230 pm, less than 220 pm, less than 210 pm, less than 200 pm, less than 180 pm, less than 160 pm, less than 140 pm, less than 120 pm, less than 100 pm, less than 80 pm, less than 70 pm, less than 60 pm, less than 50 pm, less than 40 pm, less than 30 pm, less than 25 pm, less than 20 pm.
According to another embodiment of the present invention, crystalline form-C of vortioxetine hydrobromide has a d (0.1) particle size which between 100 pm to 5 pm, a d (0.5) particle size which between 200 pm to 10 pm, a d (0.9) particle size which between 250 pm to 10 pm.
According to one embodiment of the present invention, the composition comprising crystalline form C of vortioxetine hydrobromide for use in the treatment of major depressive disorder (MDD) is formulated a solid oral dosage form or injectable form.
The pharmaceutical composition of the present invention is provided as solid oral dosage form. Solid oral dosage forms include, but are not limited to tablets, hard or soft capsules, caplets, lozenges, pills, mini-tablets, tablets, pellets, beads, granules (e.g. packaged in sachets). Compositions for solid oral dosage form are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions.
According to one embodiment of the present invention, the tablet is in the form of coated tablet, film- coated tablet, trilayer tablet, bilayer tablet, multilayer tablet, orally disintegrating tablet, mini tablet, pellet, buccal tablet, sublingual tablet, effervescent tablet, immediate release tablet, modified release tablet.
The solid oral dosage composition of the present invention comprises at least one pharmaceutically acceptable excipient which is selected from the group comprising fillers, binders, disintegrants, lubricants, glidants or mixtures thereof in order to provide the desired dissolution profile.
Suitable fillers are selected from the group comprising microcrystalline cellulose, mannitol, lactose monohydrate, starch, dibasic calcium phosphate, tribasic calcium phosphate, trehalose, isomalt, sodium carbonate, sodium bicarbonate, calcium carbonate, carboxymethyl cellulose, polydextrose, polyethylene oxide, hydroxypropyl methyl cellulose, methyl cellulose, polyethylene glycol or mixtures thereof.
According to one embodiment of the present invention, the amount of filler is between 30.0% and 95.0% by weight of the total composition.
According to one embodiment of the present invention, preferably the filler is microcrystalline cellulose or mannitol or mixtures thereof.
Suitable binders are selected from the group comprising hydroxypropyl cellulose, polyvinylpyrrolidone, sugars, alginates, carbomers, carboxymethylcellulose sodium, cellulose acetate phthalate, chitosan, copovidone, pregelatinized starch, starch mucilage, acacia mucilage, dextrates, dextrin, dextrose, ethylcellulose, glyceryl behenate, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl starch, hypromellose, magnesium aluminum silicate, maltodextrin, maltose, methylcellulose, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethacrylates, aluminia hydroxide, stearic acid, sucrose, bentonite, cetostearyl alcohol, polyoxyethilene-alkyl ethers, pullulan or mixtures thereof.
According to one embodiment of the present invention, the amount of binder is between 0.1% and 10.0% by weight of the total composition.
According to one embodiment of the present invention, preferably the binder is hydroxypropyl cellulose.
Suitable disintegrants are selected from the group comprising sodium starch glycolate, crospovidone, cross-linked carboxymethyl cellulose (croscarmellose sodium), pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, polyacryline potassium, sodium alginate, alginates, ion- exchange resins, magnesium aluminium silica, poloxamer, sodium glycine carbonate or mixtures thereof. According to one embodiment of the present invention, the amount of disintegrants is between 0.1% and 10.0% by weight of the total composition.
According to one embodiment of the present invention, preferably the disintegrants is sodium starch glycolate.
Suitable lubricants are selected from the group comprising magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, glyseryl palmito sulphate, sodium stearyl fumarate, sodium lauryl sulphate or mixtures thereof.
According to one embodiment of the present invention, the amount of the lubricant is between 0.1% and 5.0% by weight of the total composition.
According to one embodiment of the present invention, preferably the lubricant is magnesium stearate.
Suitable glidants are selected from the group comprising colloidal silicon dioxide, talc, aluminium silicate, colloidal silica, calcium silicate, magnesium silicate, magnesium oxide, starch or mixtures thereof.
According to one embodiment of the present invention, the amount of the glidant is between 0.1% and 5.0% by weight of the total composition.
According to one embodiment of the present invention, preferably the glidant is colloidal silicon dioxide.
According to one embodiment of the present invention, the composition comprising crystalline form C of vortioxetine hydrobromide for use in the treatment of major depressive disorder (MDD) is formulated an injectable form.
According to one embodiment of the present invention, injectable form is in the form of intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection, and infusion. According to one embodiment of the present invention, the injectable form comprises at least one pharmaceutically acceptable excipient selected from preservatives, surfactants, solvents or mixtures thereof. The composition of the present invention can be prepared, using standard techniques and manufacturing processes well known in the art, such as direct compression, wet or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion, spheronization, slugging, spray drying and solvent evaporation. Example 1 : A solid pharmaceutical comprising crystalline form C of vortioxetine hydrobromide
Example 2: A solid pharmaceutical comprising crystalline form C of vortioxetine hydrobromide Example 3: A film tablet comprising crystalline form C of vortioxetine hydrobromide processed by wet granulation
A process for preparing the film tablet comprising crystalline form C of vortioxetine hydrobromide in example 3 comprises the following steps: a) Mixing mannitol 60 and microcrystalline cellulose, crystalline form C of vortioxetine hydrobromide, hydroxypropyl cellulose SSL, sodium starch glycolate, b) Granulating the mixture with water-ethanol mixture, c) Drying the mixture until the humidity is less than 2.0%, then sieving the mixture d) Adding the remaining part of mannitol 60, the remaining part of sodium starch glycolate and colloidal silicon dioxide and then mixing, e) Adding magnesium stearate and then mixing, f) Then, pressing to form tablet and coating.

Claims

1. Crystalline form C of vortioxetine hydrobromide for use in the treatment of major depressive disorder (MDD).
2. Crystalline form C of vortioxetine hydrobromide for use according to 1 , wherein the form is administered in a daily dosage of from 5.0 mg to 20 mg.
3. Crystalline form C of vortioxetine hydrobromide for use according to 1 , wherein crystalline form-C of vortioxetine hydrobromide has a d (0.1) particle size which between 100 pm to 5 pm, a d (0.5) particle size which between 200 pm to 10 pm, a d (0.9) particle size which between 250 pm to 10 pm.
4. Composition comprising crystalline form C of vortioxetine hydrobromide for use in the treatment of major depressive disorder (MDD) wherein the composition is formulated a solid oral dosage form or injectable form.
5. Composition comprising crystalline form C of vortioxetine hydrobromide according to claim 4, wherein a solid oral dosage form comprising at least one pharmaceutically acceptable excipient which is selected from the group comprising fillers, binders, disintegrants, lubricants, glidants or mixtures thereof.
6. Composition comprising crystalline form C of vortioxetine hydrobromide according to claim 4, wherein the injectable form comprises at least one pharmaceutically acceptable excipient selected from preservatives, surfactants, solvents or mixtures thereof.
7. Composition comprising crystalline form C of vortioxetine hydrobromide according to claim 4, wherein the composition is prepared using direct compression, wet or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion, spheronization, slugging, spray drying or solvent evaporation.
EP21744455.3A 2020-01-23 2021-01-15 CRYSTALLINE FORM C OF VORTIOXETINE HYDROBROMO Pending EP4093402A4 (en)

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PCT/TR2021/050028 WO2021150188A1 (en) 2020-01-23 2021-01-15 Crystalline form c of vortioxetine hydrobromide

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PL2044043T5 (en) * 2006-06-16 2022-05-02 H. Lundbeck A/S 1- ý[- (2, 4-dimethylphenylsulfanyl) -phenyl]piperazine as a compound with combined serotonin reuptake, 5-ht3 and 5-ht1a activity for the treatment of cognitive impairment
US10414741B2 (en) * 2013-09-30 2019-09-17 Cadila Healthcare Limited Amorphous vortioxetine and salts thereof
AU2015254949A1 (en) * 2014-04-28 2016-10-06 Alembic Pharmaceuticals Limited Novel polymorphic forms of Vortioxetine and its pharmaceutically acceptable salts
US20190224192A1 (en) * 2016-08-29 2019-07-25 Cipla Limited Stable Pharmaceutical Composition of Vortioxetine Hydrobromide
WO2018065348A1 (en) * 2016-10-05 2018-04-12 Hexal Ag Novel enteric-coated tablet comprising vortioxetine
CN107954947A (en) * 2016-10-14 2018-04-24 北京莱瑞森医药科技有限公司 Vortioxetine hydrobromate crystal form C and preparation method thereof
US11020390B2 (en) * 2017-02-17 2021-06-01 Unichem Laboratories Ltd Bioequivalent pharmaceutical composition of vortioxetine hydrobromide

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