WO2014177491A1 - Nouvelle forme solide de bromhydrate de 1-(2-((2,4-diméthylphényl)thio)phényl)pipérazine - Google Patents

Nouvelle forme solide de bromhydrate de 1-(2-((2,4-diméthylphényl)thio)phényl)pipérazine Download PDF

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Publication number
WO2014177491A1
WO2014177491A1 PCT/EP2014/058546 EP2014058546W WO2014177491A1 WO 2014177491 A1 WO2014177491 A1 WO 2014177491A1 EP 2014058546 W EP2014058546 W EP 2014058546W WO 2014177491 A1 WO2014177491 A1 WO 2014177491A1
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WIPO (PCT)
Prior art keywords
amorphous
vortioxetine hydrobromide
adsorbent
amorphous vortioxetine
hydrobromide
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PCT/EP2014/058546
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English (en)
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Borut ZUPANCIC
Polona MULEC
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Lek Pharmaceuticals D.D.
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Publication of WO2014177491A1 publication Critical patent/WO2014177491A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • 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

Definitions

  • This invention relates to a new solid form of 1 -(2-((2,4-dimethylphenyl)thio)phenyl)piperazine hydrobromide (vortioxetine hydrobromide) a drug for the treatment of depression and anxiety
  • the invention further relates to pharmaceutical compositions comprising this new solid form, processes for the manufacture thereof and their use as medicaments.
  • a stabilised amorphous form of vortioxetine hydrobromide which shows improved solubility relative to crystalline vortioxetine hydrobromide.
  • the amorphous vortioxetine hydrobromide is stabilised by means of an adsorbent.
  • surprisingly high levels of active pharmaceutical agent (API) loading on the adsorbent can be achieved, translating into smaller tablet size when formulating the API into a pharmaceutical composition.
  • API active pharmaceutical agent
  • Figure 1 XRPD of amorphous vortioxetine hydrobromide in association with Syloid 72 FP
  • Figure 3 SEM images at 10,000x (Figure 3a) and 1 ,000x ( Figure 3b) magnifications of
  • Figure 4 SEM images at 10,000x ( Figure 4a) and 1 ,000x ( Figure 4b) magnifications of amorphous vortioxetine hydrobromide in association with Syloid 72 FP adsorbent (35% loading)
  • Figure 5 SEM images at 10,000x (Figure 5a) and 1 ,000x ( Figure 5b) magnifications of crystalline vortioxetine hydrobromide (50%) mixed with Syloid 72 FP (50%)
  • Embodiments and examples of the present invention are described below.
  • Embodiment 1 Amorphous vortioxetine hydrobromide in association with an adsorbent.
  • Embodiment 2 Amorphous vortioxetine hydrobromide according to Embodiment 1
  • the adsorbent is selected from Al 2 0 3 , CaC0 3 , MgO, Si0 2 , Ti0 2 and ZnO.
  • Embodiment 3 Amorphous vortioxetine hydrobromide according to Embodiment 1
  • the adsorbent comprises silicon
  • Embodiment 4 Amorphous vortioxetine hydrobromide according to any one of
  • Embodiments 1 to 3 wherein the adsorbent is Si0 2 .
  • Embodiment 5 Amorphous vortioxetine hydrobromide according to any one of
  • Embodiment 6 Amorphous vortioxetine hydrobromide according to Embodiment 1 or
  • Embodiment 3 wherein the adsorbent is a silicate.
  • Embodiment 7 Amorphous vortioxetine hydrobromide according to Embodiment 6
  • Embodiment 8 Amorphous vortioxetine hydrobromide according to any one of
  • Embodiments 1 to 4 wherein the adsorbent is selected from Aerosil and Syloid.
  • Embodiment 9 Amorphous vortioxetine hydrobromide according to Embodiment 8 wherein the adsorbent is selected from Aerosil 200, Aerosil 380, Syloid AL1 , Syloid 72 FP and Syloid 244 FP.
  • Embodiment 10 Amorphous vortioxetine hydrobromide according to any one of
  • Embodiments 1 to 9 wherein the loading of amorphous vortioxetine hydrobromide on the adsorbent is over 20%.
  • Embodiment 1 1 Amorphous vortioxetine hydrobromide according to any one of
  • Embodiments 1 to 9 wherein the loading of amorphous vortioxetine hydrobromide on the adsorbent is over 25%.
  • Embodiment 12 Amorphous vortioxetine hydrobromide according to any one of
  • Embodiments 1 to 9 wherein the loading of amorphous vortioxetine hydrobromide on the adsorbent is over 30%.
  • Embodiment 13 Amorphous vortioxetine hydrobromide according to any one of
  • Embodiments 1 to 9 wherein the loading of amorphous vortioxetine hydrobromide on the adsorbent is over 35%.
  • Embodiment 14 Amorphous vortioxetine hydrobromide according to any one of
  • Embodiments 1 to 9 wherein the loading of amorphous vortioxetine hydrobromide on the adsorbent is over 40%.
  • Embodiment 15 Amorphous vortioxetine hydrobromide according to any one of
  • Embodiments 1 to 9 wherein the loading of amorphous vortioxetine hydrobromide on the adsorbent is over 45%.
  • Embodiment 16 Amorphous vortioxetine hydrobromide according to any one of
  • Embodiment 10 to 15 wherein the loading of amorphous vortioxetine hydrobromide on the adsorbent is less than 60%.
  • Embodiment 17 Amorphous vortioxetine hydrobromide according to any one of
  • Embodiment 10 to 15 wherein the loading of amorphous vortioxetine hydrobromide on the adsorbent is less than 55%.
  • Embodiment 18 A pharmaceutical composition comprising amorphous vortioxetine hydrobromide as defined in any one of Embodiments 1 to 17.
  • Embodiment 19 A pharmaceutical composition according to Embodiment 18 comprising at least one pharmaceutically acceptable excipient.
  • Embodiment 20 A process for the preparation of a pharmaceutical composition comprising amorphous vortioxetine hydrobromide in association with an adsorbent which comprises:
  • Embodiment 21 A process according to Embodiment 20 wherein the adsorbent is selected from Al 2 0 3 , CaC0 3 , MgO, Si0 2 , Ti0 2 and ZnO.
  • Embodiment 22 A process according to Embodiment 21 wherein the adsorbent is Si0 2 .
  • Embodiment 23 A process according to any one of Embodiments 20 to 22 wherein the adsorbent is a silica gel.
  • Embodiment 24 A process according to Embodiment 23 wherein the silica gel is selected from Aerosil and Syloid.
  • Embodiment 25 A process according to Embodiment 24 wherein the silica gel is selected from Aerosil 200, Aerosil 380, Syloid AL1 , Syloid 72 FP and Syloid 244 FP.
  • Embodiment 26 A process according to Embodiment 20 wherein the adsorbent is a silicate.
  • Embodiment 27 A process according to Embodiment 26 wherein the silicate is Neusilin.
  • Embodiment 28 A process according to any one of Embodiments 20 to 27 wherein the solvent used in step (i) is a protic solvent selected from Ci-C 6 alcohols.
  • Embodiment 29 A process according to Embodiment 28 wherein the CrC 6 alcohol is 1 - butanol.
  • Embodiment 30 A process according to any one of Embodiments 20 to 27 wherein the solvent used in step (i) is dichloromethane.
  • Embodiment 31 A process according to any one of Embodiments 20 to 30 wherein step (i) is carried out at a temperature of 0 to 100°C.
  • Embodiment 32 A process according to any one of Embodiments 20 to 30 wherein step (i) is carried out at a temperature of 20 to 30°C.
  • Embodiment 33 A process according to any one of Embodiments 20 to 32 wherein in step
  • Embodiment 34 A process according to any one of Embodiments 20 to 33 wherein in step
  • Embodiment 35 A pharmaceutical composition according to Embodiment 18 or
  • Embodiment 19 for use as a medicament.
  • Embodiment 36 A pharmaceutical composition according to Embodiment 18 or
  • Embodiment 19 for use in the treatment of mood disorders; major depressive disorder; general anxiety disorder; post-traumatic stress disorder; depression associated with cognitive impairment, Alzheimer's disease or anxiety; depression with residual symptoms; chronic pain; or eating disorders.
  • major depressive disorder major depressive disorder
  • general anxiety disorder general anxiety disorder
  • post-traumatic stress disorder depression associated with cognitive impairment, Alzheimer's disease or anxiety
  • depression with residual symptoms chronic pain; or eating disorders.
  • amorphous vortioxetine hydrobromide is intended to mean a noncrystalline form of vortioxetine hydrobromide as determined by differential scanning calorimetry (DSC), x-ray powder diffraction (XRPD) analysis or by using a scanning electron microscope (SEM).
  • the term "in association with” is intended to mean that the amorphous vortioxetine hydrobromide forms an adsorbate on the surface of the adsorbent.
  • the difference between amorphous vortioxetine hydrobromide in association with an adsorbent and crystalline vortioxetine hydrobromide simply mixed with an adsorbent can be clearly seen using a SEM (for example see Figure 4b versus Figure 5b).
  • the term "adsorbent” is intended to mean any substance onto which amorphous vortioxetine hydrobromide is adsorbed.
  • Adsorption of amorphous vortioxetine hydrobromide onto an adsorbent serves to stabilise the vortioxetine hydrobromide in its amorphous form.
  • adsorbents include, but are not limited to, Si0 2 , Al 2 0 3 , Ti0 2 , MgO, synthetic and amorphous silicas such as Aerosil, for example Aerosil 200, Aerosil 380 (Evonik Industries), Syloid, for example Syloid AL1 , Syloid 72 FP and Syloid 244 FP (W. R. Grace & Co. -Conn), and synthetic and amorphous silicates such as Neusilin and in particular Neusilin UFL2 (Fuji Chemical industry Co., Ltd.).
  • silica gel is intended to mean a granular, porous form of Si0 2 .
  • examples of silica gels include, but are not limited to, Syloid AL1 , Syloid 72 FP and Syloid 244 FP.
  • the term "silicate” is intended to mean a compound comprising silicon, oxygen and one or more metals.
  • An example of a silicate includes, but is not limited to, Neusilin.
  • the weight of amorphous vortioxetine hydrobromide remaining in the filtrate is determined by weighing the amount of vortioxetine hydrobromide in the filtrate after solvent evaporation or by HPLC analysis of the filtrate.
  • aprotic solvent is intended to mean any solvent which contains no hydrogen atom that is capable of hydrogen bonding.
  • aprotic solvents include, but are not limited to, DMSO, DMF and CH 2 CI 2 .
  • protic solvent is intended to mean any solvent which contains one or more hydrogen atoms that are capable of hydrogen bonding.
  • protic solvents include, but are not limited to, Ci-C 6 alcohols and acetic acid.
  • the term "pharmaceutical composition” is intended to mean any mixture or solution containing amorphous vortioxetine hydrobromide in association with an adsorbent suitable for administration to a mammal, preferably a human, in order to prevent, treat or control a particular disease or condition affecting the mammal.
  • pharmaceutically acceptable excipient refers to a
  • excipients include, but are not limited to, antioxidants, binders, buffering agents, Bulking agents, disintegrants, diluents, fillers, glidants, lubricants, preservatives, surfactants and cosurfactants.
  • antioxidants antioxidants
  • binders buffering agents
  • Bulking agents disintegrants
  • diluents fillers
  • glidants lubricants
  • preservatives surfactants and cosurfactants.
  • surfactants and cosurfactants include, but are not limited to, antioxidants, binders, buffering agents, Bulking agents, disintegrants, diluents, fillers, glidants, lubricants, preservatives, surfactants and cosurfactants.
  • the amount of each excipient used may vary within ranges conventional in the art.
  • the term "subject" refers to an animal. Typically the animal is a mammal. In a preferred embodiment the subject is a human.
  • a subject is "in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
  • a therapeutically effective amount of amorphous vortioxetine hydrobromide refers to an amount of amorphous vortioxetine hydrobromide that will elicit the biological or medical response of a subject, ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent disease.
  • treat refers to ameliorating, alleviating or modulating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • WO 2007/144005 A1 states that vortioxetine, and pharmaceutically acceptable salts thereof, exert a combination of serotonin transporter (SERT), 5-HT 3 antagonism and 5-HT 1A partial agonism.
  • SERT serotonin transporter
  • 5-HT 3 antagonism 5-HT 3 antagonism
  • 5-HT 1A partial agonism 5-HT 1A partial agonism.
  • the amorphous vortioxetine hydrobromide of the present invention is expected to be of use in the treatment of mood disorders; major depressive disorder; general anxiety disorder; post-traumatic stress disorder; depression associated with cognitive impairment, Alzheimer's disease or anxiety; depression with residual symptoms; chronic pain; and eating disorders.
  • the invention in one aspect, relates to a pharmaceutical composition comprising amorphous vortioxetine hydrobromide in association with an adsorbent for use as a medicament. In one embodiment, the invention relates to a
  • composition comprising amorphous vortioxetine hydrobromide in association with an adsorbent for use in the treatment of mood disorders; major depressive disorder; general anxiety disorder; post-traumatic stress disorder; depression associated with cognitive impairment, Alzheimer's disease or anxiety; depression with residual symptoms; chronic pain; or eating disorders.
  • the invention relates to the use of amorphous vortioxetine hydrobromide as an active pharmaceutical ingredient in a medicament.
  • the invention relates to the use of amorphous vortioxetine hydrobromide as an active pharmaceutical ingredient in a medicament for the treatment of mood disorders; major depressive disorder; general anxiety disorder; post-traumatic stress disorder; depression associated with cognitive impairment, Alzheimer's disease or anxiety; depression with residual symptoms; chronic pain; or eating disorders.
  • the invention relates to the use of amorphous vortioxetine hydrobromide for the manufacture of a medicament for the treatment mood disorders; major depressive disorder; general anxiety disorder; post-traumatic stress disorder; depression associated with cognitive impairment, Alzheimer's disease or anxiety; depression with residual symptoms; chronic pain; or eating disorders.
  • the invention relates to a method for the treatment of mood disorders; major depressive disorder; general anxiety disorder; post-traumatic stress disorder;
  • Amorphous vortioxetine hydrobromide may be conveniently administered in a unit dose form comprising about 1 to 50 mg of the API.
  • the total daily dose is expected to be in the range of about 1 to 20 mg of API.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising amorphous vortioxetine hydrobromide as API in association with an adsorbent and
  • excipients comprising at least one pharmaceutically acceptable excipient.
  • excipients include, but are not limited to, antioxidants, binders, buffering agents, bulking agents, disintegrants, diluents, fillers, glidants, lubricants, preservatives, surfactants and cosurfactants.
  • Typical excipients include antioxidants.
  • Antioxidants may be used to protect ingredients of the composition from oxidizing agents that are included within or come in contact with the composition.
  • antioxidants include water soluble antioxidants such as ascorbic acid, sodium sulfite, metabisulfite, sodium miosulfite, sodium formaldehyde, sulfoxylate, isoascorbic acid, isoascorbic acid, cysteine hydrochloride, 1 ,4-diazobicyclo-(2,2,2)-octane, and mixtures thereof.
  • oil-soluble antioxidants include ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, potassium propyl gallate, octyl gallate, dodecyl gallate, phenyl-a-napthyl-amine, and tocopherols such as a-tocopherol.
  • Examples of pharmaceutically acceptable binders include, but are not limited to, starches; celluloses and derivatives thereof; copolymer of 1 -vinyl-2-pyrrolidone and vinyl acetate;
  • sucrose sucrose; dextrose; corn syrup; polysaccharides; and gelatin.
  • celluloses and derivatives thereof include for example, microcrystalline cellulose, e.g., AVICEL PH from FMC (Philadelphia, PA), hydroxypropyl cellulose hydroxylethyl cellulose and
  • hydroxylpropylmethyl cellulose METHOCEL from Dow Chemical Corp. (Midland, Ml); HP- Cellulose 100 (Klucel LF).
  • Copolymer of 1 -vinyl-2-pyrrolidone and vinyl acetate can be purchased as Kollidon VA64 from BASF.
  • Buffering agents may be used to maintain an established pH of the composition.
  • buffering agents included sodium citrate, calcium acetate, potassium metaphosphate, potassium phosphate monobasic, and tartaric acid.
  • Bulking agents are ingredients which may provide bulk to a pharmaceutical composition.
  • Examples of bulking agents include, without limitation, PEGs, mannitol, trehalose, lactose, sucrose, polyvinyl pyrrolidone, sucrose, glycine, cyclodextrins, dextran and derivatives and mixtures thereof.
  • Surfactants are agents used to stabilize multi-phasic compositions, e.g., used as wetting agents, antifoam agents, emulsifiers, dispersing agents, and penetrants.
  • Surfactants include, but are not limited to, fatty acid and alkyl sulfonates; benzethanium chloride, e.g., HYAMINE 1622 from Lonza, Inc.
  • Such surfactants e.g., minimize aggregation of lyophilized particles during reconstitution of the product.
  • Surfactants if present, are typically used in an amount of from about 0.01 % to about 5% w/v.
  • a cosurfactant is a surface-active agent that acts in addition to the surfactant by further lowering the interfacial energy but that cannot form micellar aggregates by itself.
  • Cosurfactants can be, for example, hydrophilic or lipophilic.
  • examples of a cosurfactant include, but are not limited to, cetyl alcohol and stearyl alcohol.
  • Examples of pharmaceutically acceptable disintegrants include, but are not limited to, starches, e.g. (sodium carboxymethyl starch); clays; celluloses, e.g. low substitute hydroxy propyl cellulose; alginates; gums; cross-linked polymers, e.g., cross-linked polyvinyl pyrrolidone or crospovidone, e.g., POLYPLASDONE XL from International Specialty
  • Examples of pharmaceutically acceptable fillers and pharmaceutically acceptable diluents include, but are not limited to, confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose and talc.
  • Examples of pharmaceutically acceptable lubricants and pharmaceutically acceptable glidants include, but are not limited to, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose and microcrystalline cellulose.
  • a lubricant may be present in an amount from about 0.1 % to about 5% by weight of the composition; whereas, the glidant, e.g., may be present in an amount from about 0.1 % to about 10% by weight.
  • Preservatives may also be used to protect the composition from degradation and/or microbial contamination.
  • preservatives include liquipar oil, phenoxyethanol, methyl paraben, propyl paraben, butyl paraben, isopropyl paraben, isobutyl paraben, diazolidinyl urea, imidazolidinyl urea, diazolindyl urea, benzalkonium chloride, benzethonium chloride, phenol, and mixtures thereof (e.g., liquipar oil).
  • the pharmaceutical compositions of the present invention are preferably in solid oral dosage form.
  • Solid oral dosage forms include, but are not limited to, tablets, hard or soft capsules, caplets, lozenges, pills, mini-tablets, pellets, beads, granules (e.g. packaged in sachets), or powders.
  • the pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc.
  • compositions for oral administration include an effective amount of amorphous vortioxetine hydrobromide in association with an adsorbent in the form of tablets, hard or soft capsules, caplets, lozenges, pills, mini-tablets, pellets, beads, granules (e.g. packaged in sachets), or powders.
  • Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
  • Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example, peanut oil, liquid paraffin or olive oil.
  • the pharmaceutical composition of the invention is in the form of a tablet or capsule.
  • the pharmaceutical compositions are tablets or gelatin capsules comprising amorphous vortioxetine hydrobromide in association with an adsorbent together with
  • diluents e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine;
  • lubricants e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol;
  • binders e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, copolymers of 1 -vinyl-2-pyrrolidone and vinyl acetate, sodium carboxymethylcellulose and/or polyvinylpyrrolidone;
  • disintegrants e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; celluloses; cross-linked polymers; and/or
  • Tablets may be either film coated or enteric coated according to methods known in the art.
  • Tablets can be optionally coated with a functional or non-functional coating as known in the art.
  • coating techniques include, but are not limited to, sugar coating, film coating, microencapsulation and compression coating.
  • Types of coatings include, but are not limited to, enteric coatings, sustained release coatings, controlled-release coatings.
  • Anhydrous pharmaceutical compositions and dosage forms can also be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
  • An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits.
  • suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e. g., vials), blister packs, and strip packs.
  • a unit dosage form is a single dosage form which has the capacity of being administered to a subject to be effective, and which can be readily handled and packaged, remaining as a physically and chemically stable unit dose comprising the active ingredient.
  • Tablets may be manufactured by direct compression or granulation.
  • the powdered materials included in the solid dosage form are typically compressed directly without modifying their physical nature.
  • the active ingredient, excipients such as a glidant to improve the rate of flow of the tablet granulation, and lubricant to prevent adhesion of the tablet material to the surface of the dies and punches of the tablet press are blended in a twin shell blender or similar low shear apparatus before being compressed into tablets.
  • Granulation is a process in which granulates are formed. These granulates are then subjected to direct compression in order to form a tablet or encapsulated for a capsule.
  • the granulates may be formed by wet granulation which includes: a) forming a powder mixture of the active ingredient and at least one
  • the granulates may be formed by fluid-bed granulation which includes:
  • a material e.g., an inert material or the active ingredient
  • melt granulation Another alternative for producing granulates includes melt granulation. This process includes:
  • at least one release retardant e.g. a release retarding polymer, and optionally, a plasticizer
  • the "softening temperature” refers to the temperature at which the release retardant experiences a change in the rate of viscosity decrease as a function of temperature
  • Another alternative for producing granulates includes dry granulation which may include roller compaction or slugging.
  • Roller compaction is a process in which uniformly mixed powders are compressed between two counter-rotating roll pairs to form a compressed sheet or ribbon that is then milled (granulated).
  • Slugging is a process in which uniformly mixed powders are compressed into large tablets which are subsequently comminuted into the desired size.
  • Capsules as used herein refer to a formulation in which the amorphous vortioxetine hydrobromide in association with an adsorbent may be enclosed in either a hard or soft, soluble container or shell, often formed from gelatin.
  • a hard gelatin capsule also known as a dry-filled capsule, is composed of two sections, one slipping over the other, thus completely surrounding (encapsulating) the drug formulation.
  • a soft elastic capsule has a soft, globular, e.g., gelatin shell.
  • X-ray powder diffraction patterns were obtained by methods known in the art using Philips X'Pert PRO diffracto meter with X'Celerator detector using CuKa radiation (tube operating at 45 kV and 40 mA) in the Bragg-Brentano (reflection) geometry. Data were recorded from 2 to 40 °2 ⁇ in steps of 0.033 °2 ⁇ and a measurement time of 50 seconds per step. Variable divergence and antiscatter slits were used to maintain 10 mm of sample length irradiated.
  • DSC thermograms were obtained using a Mettler Toledo DSC822e differential scanning calorimeter. The sample (1 -10 mg) was placed in an unsealed aluminium pan with a hole and heated at 10°C/min in the temperature range from 30 °C to 250 °C.
  • the samples were mounted on stubs with double faced adhesive tape and sputter coated with a 3 nm gold layer in a high vacuum sputter coater (Leica EM SCD 500).
  • Surface topography was analyzed with a scanning electron microscope (JSM FE SEM 7001 , Jeol, Tokyo, Japan) using secondary electron imaging (SEI) detector and different magnifications (100 - 20 OOOx).
  • SEI secondary electron imaging
  • Example 1 Preparation of amorphous vortioxetine HBr on Syloid 72 FP Crystalline vortioxetine HBr was dissolved in dichloromethane at room temperature (a temperature range of about 21 °C to 26°C). Syloid 72 FP was added, the mixture stirred for 15 minutes at room temperature and the slurry then filtered. The dry product was analyzed by DSC and XPRD and found to be amorphous as shown in Table 1 below.
  • FIG. 1 shows an XRPD of amorphous vortioxetine HBr in association with Syloid 72 FP when 0.2 g of vortioxetine HBr was dissolved in 5 mL dichloromethane and mixed with 0.2 g Syloid 72 FP to achieve a 17.6% loading. Similar XRPDs indicative of amorphous material were obtained for the other preparations listed in Table 1. The XRPDs obtained for amorphous vortioxetine HBr are in sharp contrast to those disclosed in WO 2007/144005 A1 for crystalline forms of vortioxetine HBr. b The cake was washed with 4 mL of CH 2 CI 2 and dried under reduced pressure at 30°C.
  • Example 2 Preparation of amorphous vortioxetine HBr on Syloid 72 FP
  • 0.2 g of crystalline vortioxetine HBr was dissolved in 10 mL of 2-propanol at 79°C and 0.2 g of Syloid 72 FP added. The mixture was stirred for 15 minutes at 79°C and the hot slurry filtered. The cake was washed with 2 mL of 2-propanol and then dried under reduced pressure at 40°C. The dry product was analyzed by DSC: amorphous.
  • 0.2 g of crystalline vortioxetine HBr was dissolved in 25 mL of n-pentanol at 33°C and 0.2 g of Syloid 72 FP added. The mixture was stirred for 15 minutes at 33°C and the slurry filtered. The cake was washed with 1 mL of n-pentanol and dried under reduced pressure at 40°C. The dry product was analyzed by DSC: amorphous.
  • Crystalline vortioxetine HBr (0.2 g) was dissolved in dichloromethane (20 mL) at room temperature (a temperature range of about 21 °C to 26°C) and Syloid 72 FP added. The mixture was stirred for 1 hour at room temperature. The solvent was then completely evaporated on a rotary evaporator under reduced pressure and at a bath temperature of 40°C. The dry product was analyzed by DSC or XPR) and found to be amorphous as shown in Table 3 below. Table 3
  • FIG. 2 shows an XRPD of amorphous vortioxetine HBr in association with Syloid 72 FP when 0.2 g of vortioxetine HBr was dissolved in 20 mL dichloromethane and mixed with 0.3 g Syloid 72 FP to achieve a 34.8% loading. Similar XRPDs indicative of amorphous material were obtained for the other preparations listed in Table 3. SEM images of amorphous vortioxetine hydrobromide in association with Syloid 72 FP adsorbent at a 35% loading are shown in Figure 4.
  • Crystalline vortioxetine HBr (0.2 g) was dissolved in dichloromethane (10 mL) at room temperature (a temperature range of about 21 °C to 26°C) and Syloid AL-1 added. The mixture was stirred for 15 hours at room temperature and the slurry filtered. The product was dried under reduced pressure at 50°C and the dry product analyzed by DSC and found to be amorphous as shown in Table 4 below.
  • Example 8 Stability of amorphous vortioxetine HBr on Syloid 72 FP
  • Crystalline vortioxetine HBr (0.2 g) was dissolved in dichloromethane (10 mL) at room temperature (a temperature range of about 21 °C to 26°C) and then carrier added. The mixture was stirred for 1 hour at room temperature. The solvent was then completely evaporated on a rotary evaporator under reduced pressure and a bath temperature of 40°C. The dry product was analyzed by DSC and found to be amorphous as shown in Table 6 below.
  • Crystalline vortioxetine HBr (0.2 g) was dissolved in 1 -butanol (10 mL) at 90°C and then Syloid 72 FP added. The mixture was stirred for 15 minutes. After cooling to room temperature the slurry was filtered. The product was dried under reduced pressure at 40°C and analyzed by DSC and found to be amorphous as shown in Table 7 below.
  • Example 11 Preparation of amorphous vortioxetine HBr on Syloid 72 FP Crystalline vortioxetine HBr (0.2 g) was dissolved in 2-propanol (10 mL) at 81 °C and Syloid 72 FP added. The mixture was stirred for 15 minutes at 81 °C and the hot slurry filtered. The product was dried under reduced pressure at 40°C and analyzed by DSC and found to be amorphous as shown in Table 8 below. Table 8
  • the sample aliquots were withdrawn through a syringe, filtered through Millipore filter (0.45 ⁇ , PVDF) and diluted.
  • the sample aliquots were analyzed for the dissolved vortioxetine HBr content using reversed-phase HPLC.
  • the concentration of dissolved vortioxetine HBr was determined from the area of vortioxetine HBr peak using a preformed calibration curve.
  • a standard curve for vortioxetine HBr was measured over a range of 200 - 0.1 ⁇ g/mL and shown to be linear.
  • Amorphous vortioxetine HBr on Syloid 72 FP was found to be more soluble than crystalline vortioxetine HBr ( Figure 6).

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Abstract

L'invention concerne une nouvelle forme solide de bromhydrate de 1-(2-((2,4-diméthylphényl)thio)phényl)pipérazine (bromhydrate de vortioxétine,un médicament pour le traitement de la dépression et de l'anxiété) sous une forme amorphe et en association avec un adsorbant. L'invention concerne aussi des compositions pharmaceutiques comprenant du bromhydrate de 1-(2-((2,4-diméthylphényl)thio)phényl)pipérazine amorphe en association avec un adsorbant, des procédés pour la fabrication de telles compositions pharmaceutiques et leur utilisation en tant que médicaments.
PCT/EP2014/058546 2013-04-29 2014-04-28 Nouvelle forme solide de bromhydrate de 1-(2-((2,4-diméthylphényl)thio)phényl)pipérazine WO2014177491A1 (fr)

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Cited By (15)

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Publication number Priority date Publication date Assignee Title
WO2015044963A1 (fr) * 2013-09-30 2015-04-02 Cadila Healthcare Limited Vortioxétine amorphe et sels de ladite substance
CN104586756A (zh) * 2015-01-05 2015-05-06 万特制药(海南)有限公司 一种含沃替西汀的口服溶液及其制备方法
WO2016116077A1 (fr) 2015-01-21 2016-07-28 Zentiva, K.S. Formes amorphes de la vortioxétine stabilisées dans des polymères
WO2016125190A2 (fr) 2015-02-04 2016-08-11 Mylan Laboratories Limited Nouvelles formes cristallines de vortioxétine, prémélanges, et procédés pour la préparation de ceux-ci
CN106279065A (zh) * 2015-05-12 2017-01-04 北京深蓝海生物医药科技有限公司 一种氢溴酸沃替西汀的精制转晶方法
CN106491604A (zh) * 2015-09-07 2017-03-15 常州方楠医药技术有限公司 一种无定型沃替西汀或其盐与药用辅料的组合物及其制备方法
WO2017041680A1 (fr) * 2015-09-07 2017-03-16 常州方楠医药技术有限公司 Composition pharmaceutique à base de vortioxétine ou d'un sel de celle-ci, et son procédé de préparation
WO2017045655A1 (fr) * 2015-09-16 2017-03-23 Zentiva, K.S. Forme amorphe de bromhydrate de vortioxétine stabilisée par une cyclodextrine
WO2017088841A1 (fr) 2015-11-26 2017-06-01 Zentiva, K.S. Préparation d'une forme médicamenteuse contenant de l'apixaban amorphe
EP3184104A1 (fr) * 2015-12-23 2017-06-28 Hexal AG Composition pharmaceutique de bromhydrate vortioxetine qui est contenu dans une matrice d'oxyde de polyéthylène
EP3209297A1 (fr) * 2014-10-24 2017-08-30 Hexal Aktiengesellschaft Bromhydrate de vortioxétine amorphe
CN107638425A (zh) * 2016-07-21 2018-01-30 常州爱诺新睿医药技术有限公司 一种新的含无定型沃替西汀氢溴酸盐的药用组合物及其制备方法
WO2018042168A1 (fr) 2016-08-29 2018-03-08 King, Lawrence Composition pharmaceutique stable de bromhydrate de vortioxétine
CN110279666A (zh) * 2019-05-20 2019-09-27 湖北万润医药有限公司 一种盐酸曲美他嗪片及其制备方法
US10519121B2 (en) 2016-12-30 2019-12-31 Apicore Us Llc Process and novel polymorphic form of vortioxetine and its pharmaceutically acceptable salts

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Cited By (20)

* Cited by examiner, † Cited by third party
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US20160214949A1 (en) * 2013-09-30 2016-07-28 Cadila Healthcare Limited An amorphous vortioxetine and salts thereof
US10414741B2 (en) 2013-09-30 2019-09-17 Cadila Healthcare Limited Amorphous vortioxetine and salts thereof
WO2015044963A1 (fr) * 2013-09-30 2015-04-02 Cadila Healthcare Limited Vortioxétine amorphe et sels de ladite substance
EP3209297A1 (fr) * 2014-10-24 2017-08-30 Hexal Aktiengesellschaft Bromhydrate de vortioxétine amorphe
CN104586756A (zh) * 2015-01-05 2015-05-06 万特制药(海南)有限公司 一种含沃替西汀的口服溶液及其制备方法
WO2016116077A1 (fr) 2015-01-21 2016-07-28 Zentiva, K.S. Formes amorphes de la vortioxétine stabilisées dans des polymères
WO2016125190A3 (fr) * 2015-02-04 2016-09-29 Mylan Laboratories Limited Nouvelles formes cristallines de vortioxétine, prémélanges, et procédés pour la préparation de ceux-ci
WO2016125190A2 (fr) 2015-02-04 2016-08-11 Mylan Laboratories Limited Nouvelles formes cristallines de vortioxétine, prémélanges, et procédés pour la préparation de ceux-ci
CN106279065A (zh) * 2015-05-12 2017-01-04 北京深蓝海生物医药科技有限公司 一种氢溴酸沃替西汀的精制转晶方法
WO2017041680A1 (fr) * 2015-09-07 2017-03-16 常州方楠医药技术有限公司 Composition pharmaceutique à base de vortioxétine ou d'un sel de celle-ci, et son procédé de préparation
CN106491604A (zh) * 2015-09-07 2017-03-15 常州方楠医药技术有限公司 一种无定型沃替西汀或其盐与药用辅料的组合物及其制备方法
WO2017045655A1 (fr) * 2015-09-16 2017-03-23 Zentiva, K.S. Forme amorphe de bromhydrate de vortioxétine stabilisée par une cyclodextrine
WO2017088841A1 (fr) 2015-11-26 2017-06-01 Zentiva, K.S. Préparation d'une forme médicamenteuse contenant de l'apixaban amorphe
EP3184104A1 (fr) * 2015-12-23 2017-06-28 Hexal AG Composition pharmaceutique de bromhydrate vortioxetine qui est contenu dans une matrice d'oxyde de polyéthylène
US10485799B2 (en) 2015-12-23 2019-11-26 Hexal Ag Pharmaceutical composition of vortioxetine hydrobromide comprising vortioxetine hydrobromide in a polyethylene oxide matrix
CN107638425A (zh) * 2016-07-21 2018-01-30 常州爱诺新睿医药技术有限公司 一种新的含无定型沃替西汀氢溴酸盐的药用组合物及其制备方法
WO2018042168A1 (fr) 2016-08-29 2018-03-08 King, Lawrence Composition pharmaceutique stable de bromhydrate de vortioxétine
US10519121B2 (en) 2016-12-30 2019-12-31 Apicore Us Llc Process and novel polymorphic form of vortioxetine and its pharmaceutically acceptable salts
CN110279666A (zh) * 2019-05-20 2019-09-27 湖北万润医药有限公司 一种盐酸曲美他嗪片及其制备方法
CN110279666B (zh) * 2019-05-20 2022-05-13 湖北万润医药有限公司 一种盐酸曲美他嗪片及其制备方法

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