WO2018065348A1 - Nouveau comprimé à enrobage entérique comprenant de la vortioxétine - Google Patents

Nouveau comprimé à enrobage entérique comprenant de la vortioxétine Download PDF

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Publication number
WO2018065348A1
WO2018065348A1 PCT/EP2017/074947 EP2017074947W WO2018065348A1 WO 2018065348 A1 WO2018065348 A1 WO 2018065348A1 EP 2017074947 W EP2017074947 W EP 2017074947W WO 2018065348 A1 WO2018065348 A1 WO 2018065348A1
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Prior art keywords
api
μηη
pharmaceutical composition
starch
composition according
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PCT/EP2017/074947
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English (en)
Inventor
Andreas Krekeler
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Hexal Ag
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Publication of WO2018065348A1 publication Critical patent/WO2018065348A1/fr

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    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates

Definitions

  • Novel enteric-coated tablet comprising vortioxetine
  • the present invention relates to a novel enteric-coated tablet comprising vortioxetine as well as the preparation thereof.
  • 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.
  • compositions 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.
  • 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)
  • the tablet core being coated with a pH sensitive coating
  • said API has a particle size distribution of D90 of 100 ⁇ or less, or
  • composition according to item 1 wherein said API has a particle size distribution of D90: 35-45 ⁇ or less, D90: 25-35 ⁇ or less, or D90: 15-25 ⁇ or less.
  • 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.
  • 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.
  • composition according to item 3 or 4, wherein the temperature of the environment is 37.0 ⁇ 0.5°C.
  • 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 polyacrylamides, phthalate derivatives, styrene and maleic acid copolymers, polyacrylic acid derivatives, methacrylic acid copolymers, vinyl acetate and crotonic acid copolymers;
  • 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 item 9 wherein the API has an XRPD pattern with reflections (expressed in 2 ⁇ ⁇ 0,2° 2 ⁇ (CuKa radiation)) at 6.89°, 9.73°, 13.78°, and 14.62°.
  • 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 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;
  • 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;
  • 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;
  • HPC hydroxypropylcellulose
  • MC methylcellulose
  • HPMC hypromellose
  • PVP povidone
  • tragacanth sodium alginate, gum arabic, starch pregelatinized, gelatin, and cellulosic derivatives, preferably HPC and/or copovidone
  • 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)
  • the process comprising the steps of: providing said API having a particle size distribution of a D90 of 100 ⁇ or less, or D90 of 45 ⁇ or less, measured by laser diffraction;
  • the method according to item 17 wherein the particle size distribution has a particle size distribution of D90: 35-45 ⁇ or less, D90: 25-35 ⁇ or less, or D90: 15-25 ⁇ 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 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 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;
  • 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;
  • 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
  • HPC hydroxypropylcellulose
  • MC methylcellulose
  • HPMC hypromellose
  • PVP povidone
  • tragacanth sodium alginate
  • gum arabic starch
  • pregelatinized, gelatin, and cellulosic derivatives preferably HPC and/or copovidone
  • 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 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.
  • 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.
  • 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.
  • 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
  • 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 ⁇ , D98: 370-390 m, D98: 100-125 ⁇ , or D98: 50-70 ⁇ .
  • 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).
  • 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.
  • 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.
  • the tablet core is coated with a pH sensitive coating and the API has a particle size distribution of D90 of 100 ⁇ or less, measured by laser diffraction.
  • 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.
  • glidants flow aids
  • lubricants to ensure efficient tableting
  • disintegrants to promote tablet break-up in the digestive tract
  • sweeteners or flavours to enhance taste
  • 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.
  • 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.
  • API active pharmaceutical ingredient
  • active pharmaceutical ingredient refers 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.
  • 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.
  • the median value is defined as the value where half of the population resides above this point, and half resides below this point.
  • 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.
  • 90 percent of the distribution lies below the D90
  • 10 percent of the population lies below the D10.
  • the API according to the present invention has a particle size distribution of D90: 100 ⁇ or less.
  • the API according to the present invention has a particle size distribution of D90: 35-45 ⁇ or less, D90: 25-35 ⁇ or less, D90: 15-25 ⁇ or less, or D90: 10-15 ⁇ or less.
  • the particle size distribution of the API has a D90 of at most 25-35 ⁇ , a D90 of at most 15-25 ⁇ , and/or a D90 of at most 10-15 ⁇ .
  • the particle size distribution of the API has a D90 of 25-35 ⁇ , a D90 of 15-25 ⁇ , or a D90 of 10-15 ⁇ .
  • the invention provides a solid form of 1 - ⁇ 2-[(2,4- dimethylphenyl)sulfanyl]phenyl ⁇ piperazine, having a D90 value of from about 10 ⁇ to about 45 ⁇ .
  • the API has a primary particle size distribution characterized by a D90 value of: from about 10 ⁇ to about 100 ⁇ ; from about 10 ⁇ to about 90 ⁇ , from about 10 ⁇ to about 80 ⁇ , from about 10 ⁇ to about 70 ⁇ , from about 10 ⁇ to about 60 ⁇ , from about 10 ⁇ to about 50 ⁇ , from about 10 ⁇ to about 45 ⁇ , from about 10 ⁇ to about 40 ⁇ , from about 10 ⁇ to about 35 ⁇ , from about 10 ⁇ to about 30 ⁇ , from about 10 ⁇ to about 25 ⁇ , from about 10 ⁇ to about 20 ⁇ , or from about 10 ⁇ to about 15 ⁇ .
  • the API has a primary particle size distribution characterized by a D90 value of: from about 10 ⁇ to about 45 ⁇ , from about 10 ⁇ to about 40 ⁇ , from about 10 ⁇ to about 35 ⁇ , from about 10 ⁇ to about 30 ⁇ , from about 10 ⁇ to about 25 ⁇ , from about 10 ⁇ to about 20 ⁇ , or from about 10 ⁇ to about 15 ⁇ .
  • the API can have a primary particle size distribution characterized by a D90 value of: from about 20 ⁇ to about 45 ⁇ , from about 20 ⁇ to about 40 ⁇ , from about 20 ⁇ to about 35 ⁇ , from about 20 ⁇ to about 30 ⁇ , or from about 20 ⁇ to about 25 ⁇ .
  • the API can have a primary particle size distribution characterized by a D90 value of: from about 30 ⁇ to about 45 ⁇ , from about 30 ⁇ to about 40 ⁇ , or from about 30 ⁇ to about 35 ⁇ .
  • the API can have a primary particle size distribution characterized by a D90 value of: from about 35 ⁇ to about 45 ⁇ , or from about 35 ⁇ to about 40 ⁇ .
  • D90 as used herein means that 90% of the particles (based on volume) are smaller than or equal to the indicated size.
  • API particles may be obtained by milling as known in the art.
  • particles may be milled in a Retsch Ball Mill with a 35 ml chamber for 10 min at a frequency of 25 Hz.
  • 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.
  • 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.
  • the following parameters may be used:
  • Particle refractive index 1 .58.
  • Feed rate 80%.
  • Feed tray Standard venture.
  • Width of sample tray 1.0 mm.
  • Disperser pressure 2 bar.
  • 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.
  • 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.
  • the above-mentioned pharmaceutically acceptable salt is vortioxetine hydrobromide.
  • the above-mentioned API may be present in a crystalline form.
  • the API is vortioxetine hydrobromide having an XRPD pattern with characteristic peaks (expressed in 2 ⁇ ⁇ 0,2° 2 ⁇ (CuKa radiation)) at 5.5°, 14.8°, 16.7° and 20.0°, and more preferably an XRPD pattern with characteristic peaks (expressed in 2 ⁇ ⁇ 0,2° 2 ⁇ (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 .
  • the API is crystalline vortioxetine hydrobromide having an XRPD pattern with reflections (expressed in 2 ⁇ ⁇ 0,2° 2 ⁇ (CuKa radiation)) at 6.89°, 9.73°, 13.78°, and 14.62°.
  • 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.
  • 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.
  • 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.
  • 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.
  • the tablet comprises the API corresponding to 5 mg vortioxetine base.
  • the tablet comprises 10, 15, or 20 mg.
  • 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.
  • 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.
  • HPC hydroxypropyl cellulose
  • MC methylcellulose
  • HPMC hypromellose
  • povidone povidone
  • tragacanth sodium alginate, gum arabic, gelatin, and starch pregelatinized.
  • 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
  • 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.
  • 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
  • the lubricant is magnesium stearate.
  • the tablet core comprises the above- mentioned API, a filler, a disintegrant, a granulation polymer (binder) and a lubricant.
  • the above-defined excipients are comprised in the tablet core in the following amounts (% by weight): API: 2-20%
  • Granulation polymer 0-10%
  • the above-mentioned tablet core may be prepared by any method known in the art.
  • the tablet core is prepared by direct compression.
  • the tablet core is prepared by dry compaction.
  • the tablet core is prepared by wet granulation.
  • any pH sensitive coating known in the art can be used for a tablet according to the invention.
  • 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.
  • the pH sensitive polymer is preferably selected from a group consisting of polyacrylamides, phthalate derivatives, styrene and maleic acid copolymers, polyacrylic acid derivatives
  • the coating comprises HPMCAS-MG, triethylcitrate and talc.
  • 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.
  • the coating comprises cellulose acetate phthalate (CAP) polymer, also known as Aquacoat® CPD used as an 30% aqueous dispersion of CAP, and diethyl phthalate.
  • CAP cellulose acetate phthalate
  • the pH sensitive coating may be applied by any method known in the art. Typically, a film coating step is applied.
  • 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.
  • excipients such as diluents, sweeteners, buffering agents, glidants, flowing agents, flavouring agents, preservatives, surfactants, wetting agents, and thickeners.
  • 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.
  • release 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.
  • release rate or "release profile” refers to the (percentage) amount released per time unit from the dosage form comprising the pharmaceutical composition.
  • 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.
  • defined time points e.g. 20 min, 40 min, 60 min, 80 min, 100 min, and 120 min
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Formulation A 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.
  • 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
  • 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.
  • Figure 1 summarizes the dissolution rate of Formulation A compared to Formulation B at pH 6.8
  • 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).
  • 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
  • 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.
  • 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).
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne un comprimé à enrobage entérique comprenant de la vortioxétine ou un sel pharmaceutiquement acceptable de celle-ci en tant qu'ingrédient pharmaceutique actif (API), l'API ayant une distribution de taille de particule de D90 inférieur ou égal à 100 µm. En outre, l'invention concerne un procédé de fabrication dudit comprimé.
PCT/EP2017/074947 2016-10-05 2017-10-02 Nouveau comprimé à enrobage entérique comprenant de la vortioxétine WO2018065348A1 (fr)

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EP16192390.9 2016-10-05

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111686083A (zh) * 2020-06-10 2020-09-22 石药集团中奇制药技术（石家庄）有限公司 一种艾普拉唑肠溶片
WO2021043227A1 (fr) * 2019-09-04 2021-03-11 普济生物科技（台州）有限公司 Granulé enrobé, dispersion solide et préparation contenant du bromhydrate de vortioxétine pour masquage du goût par voie orale
WO2021150188A1 (fr) * 2020-01-23 2021-07-29 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Forme cristalline c de bromhydrate de vortioxétine

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007144005A1 (fr) 2006-06-16 2007-12-21 H. Lundbeck A/S 1-[2-(2, 4-diméthylphénylsulfanyl)-phényl]pipérazine comme composé présentant une activité sur la sérotonine, 5-ht3 et 5-ht1a pour le traitement du déficit cognitif
WO2011023194A2 (fr) 2009-08-24 2011-03-03 H. Lundbeck A/S Nouvelles compositions de 1-[2-(2,4-diméthyl-phénylsulfanyl)-phényl]pipérazine
EP2564838A1 (fr) 2010-04-30 2013-03-06 Takeda Pharmaceutical Company Limited Comprimé à délitage intestinal
WO2014044721A1 (fr) 2012-09-19 2014-03-27 Sandoz Ag Nouvelle forme cristalline de bromhydrate de vortioxétine
WO2014161976A1 (fr) 2013-04-04 2014-10-09 Lek Pharmaceuticals D.D. Nouveau procédé pour la synthèse de 1-(2-((2,4-diméthylphényl)thio)phényl)pipérazine
WO2014191548A1 (fr) 2013-05-31 2014-12-04 Lek Pharmaceuticals D.D. Nouveau procédé pour la synthèse de 1-(2-((2,4-diméthylphényl)thio)phényl)pipérazine
WO2015000833A1 (fr) * 2013-07-01 2015-01-08 Lek Pharmaceuticals D.D. Acétate de 1-[2-(2,4-diméthylphénylsulfanyl)phényl]pipérazine sous forme cristalline

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007144005A1 (fr) 2006-06-16 2007-12-21 H. Lundbeck A/S 1-[2-(2, 4-diméthylphénylsulfanyl)-phényl]pipérazine comme composé présentant une activité sur la sérotonine, 5-ht3 et 5-ht1a pour le traitement du déficit cognitif
WO2011023194A2 (fr) 2009-08-24 2011-03-03 H. Lundbeck A/S Nouvelles compositions de 1-[2-(2,4-diméthyl-phénylsulfanyl)-phényl]pipérazine
EP2564838A1 (fr) 2010-04-30 2013-03-06 Takeda Pharmaceutical Company Limited Comprimé à délitage intestinal
WO2014044721A1 (fr) 2012-09-19 2014-03-27 Sandoz Ag Nouvelle forme cristalline de bromhydrate de vortioxétine
WO2014161976A1 (fr) 2013-04-04 2014-10-09 Lek Pharmaceuticals D.D. Nouveau procédé pour la synthèse de 1-(2-((2,4-diméthylphényl)thio)phényl)pipérazine
WO2014191548A1 (fr) 2013-05-31 2014-12-04 Lek Pharmaceuticals D.D. Nouveau procédé pour la synthèse de 1-(2-((2,4-diméthylphényl)thio)phényl)pipérazine
WO2015000833A1 (fr) * 2013-07-01 2015-01-08 Lek Pharmaceuticals D.D. Acétate de 1-[2-(2,4-diméthylphénylsulfanyl)phényl]pipérazine sous forme cristalline

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021043227A1 (fr) * 2019-09-04 2021-03-11 普济生物科技（台州）有限公司 Granulé enrobé, dispersion solide et préparation contenant du bromhydrate de vortioxétine pour masquage du goût par voie orale
WO2021150188A1 (fr) * 2020-01-23 2021-07-29 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Forme cristalline c de bromhydrate de vortioxétine
CN111686083A (zh) * 2020-06-10 2020-09-22 石药集团中奇制药技术（石家庄）有限公司 一种艾普拉唑肠溶片

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