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WO2016116077A1 - Formes amorphes de la vortioxétine stabilisées dans des polymères - Google Patents

Formes amorphes de la vortioxétine stabilisées dans des polymères Download PDF

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Publication number
WO2016116077A1
WO2016116077A1 PCT/CZ2016/000008 CZ2016000008W WO2016116077A1 WO 2016116077 A1 WO2016116077 A1 WO 2016116077A1 CZ 2016000008 W CZ2016000008 W CZ 2016000008W WO 2016116077 A1 WO2016116077 A1 WO 2016116077A1
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WO
WIPO (PCT)
Prior art keywords
vortioxetine
polymer
hydrobromide salt
amorphous
mixture
Prior art date
Application number
PCT/CZ2016/000008
Other languages
English (en)
Inventor
Pavel ZVATORA
Ondrej Dammer
Michal Benes
Lukas KREJCIK
Jaroslava SVOBODOVA
Robert Klvana
Original Assignee
Zentiva, K.S.
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 Zentiva, K.S. filed Critical Zentiva, K.S.
Publication of WO2016116077A1 publication Critical patent/WO2016116077A1/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
    • A61K9/146—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 organic macromolecular compounds

Definitions

  • This invention relates to new amorphous forms of l-(2-((2,4-dimethylphenyl)- thio)phenyl)piperazine, known as vortioxetine (formula I)
  • the invention further encompasses various methods of preparing the amorphous forms and their use for a pharmaceutical composition.
  • Vortioxetine is used in pharmacy for the treatment of depression and anxiety. Its synthesis and use were first described in the application WO 03029232. In a more recent application, WO 2007/144005, various crystalline salts of vortioxetine are described and characterized, as well as their use in a pharmaceutical composition. In particular, e.g. solubilities of crystalline forms of vortioxetine hydrobromide alpha (2 mg/ml) and beta (1.2 mg/ml) are compared.
  • a new application describes amorphous forms of vortioxetine hydrobromide stabilized by adsorbents such as A1 2 0 3 , CaC0 3 , MgO, Si0 2 , Ti0 2 and ZnO. These amorphous forms have a higher solubility and biological availability than crystalline vortioxetine hydrobromide.
  • the present invention wherein the amorphous forms of vortioxetine or vortioxetine hydrobromide are stabilized by means of a polymer, is more advantageous, compared to the use of adsorbents of WO 2014/177491, mainly in that the solubility of polymers is dependent on the pH value of the solution, which means that their use makes it possible to influence releasing of the pharmaceutically active substance depending on pH of the alimentary tract.
  • the invention provides amorphous mixtures of vortioxetine and vortioxetine hydrobromide with suitable polymeric carriers such as cellulose derivatives, polyacrylates or methacrylates and poly vinyl derivatives, processes of their preparation and their use for a pharmaceutical composition.
  • suitable polymeric carriers such as cellulose derivatives, polyacrylates or methacrylates and poly vinyl derivatives
  • Figure 1 X-ray powder pattern of vortioxetine base with Eudragit L 100 (weight ratio 1:2, API: polymer)
  • Figure 2 X-ray powder pattern of vortioxetine base with Eudragit S 100 (weight ratio 1 :2, API: polymer)
  • Figure 3 X-ray powder pattern of vortioxetine base with HPMCAS LF (weight ratio 1 :2, API: polymer)
  • Figure 4 X-ray powder pattern of vortioxetine hydrobromide with Eudragit L 100 (weight ratio 1:2, API: polymer)
  • Figure 5 X-ray powder pattern of vortioxetine hydrobromide with Eudragit S 100 (weight ratio 1:2, API: polymer)
  • Figure 6 X-ray powder pattern of vortioxetine hydrobromide with HPMCAS LF (weight ratio 1:2, API: polymer)
  • Figure 7 X-ray powder pattern of vortioxetine hydrobromide with PVP K30 (weight ratio 1 :2, API: polymer)
  • Figure 8 X-ray powder pattern of vortioxetine hydrobromide with Methocel E5 (weight ratio 1:2, API: polymer)
  • the invention relates to new solid forms of l-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine, known as vortioxetine, and to vortioxetine hydrobromide, in the form of a stable amorphous mixture with a polymer, and to methods of preparing the same.
  • a crystalline solid is characterized by a long-distance structure arrangement. On the other hand, amorphous solids do not exhibit this arrangement.
  • the molecular arrangement of an amorphous solid may be represented by a "frozen liquid" with rheological properties of a solid.
  • solid dispersion represents any solid composition consisting of at least two components.
  • the solid dispersion contains the pharmaceutically active ingredient (vortioxetine, or its salt), which is dispersed in at least one component, e.g. in a polymer.
  • molecular dispersion refers to dispersion of a component (e.g. vortioxetine) with a polymeric matrix.
  • a component e.g. vortioxetine
  • vortioxetine or its salt may be dispersed in the polymeric matrix in such a way that they are immobilized in this matrix in their amorphous form.
  • Tg glass transition temperature
  • vitreous solution it is referred to as a vitreous solution.
  • vitreous suspension In case the component (vortioxetine, or its salt) is dispersed in the polymeric matrix in the form of amorphous clusters, this solid dispersion is referred to as a vitreous suspension.
  • the resulting vitreous suspension has two or more glass transitions, which belong to the amorphous active pharmaceutical substance and to the particular polymer or polymers.
  • amorphous solids As mentioned above, compared to crystalline solids, amorphous solids have a different internal structure and a larger surface area, and therefore they exhibit a higher solubility. If the solubility and biological availability of pharmaceutically active substances needs to be increased, they should be preferably prepared in an amorphous form.
  • the glass transition temperature is at least 20°C, preferably 30°C and most preferably at least 40°C above the temperature of the actual storage conditions.
  • Amorphous vortioxetine which is not stabilized, has a low glass transition temperature (-8°C).
  • the glass transition temperature of the amorphous non- stabilized form is 64°C.
  • Amorphous forms of vortioxetine or vortioxetine hydrobromide can be stabilized by addition of other substances. A number of substances may be used as stabilizers of the amorphous state.
  • the application WO 2014/17749 describes amorphous forms of vortioxetine hydrobromide stabilized with the adsorbents AI 2 0 , CaC0 3 ⁇ MgO, Si0 2 , Ti0 2 , ZnO.
  • a suitable polymer may come from the groups of water-soluble or water-insoluble polymers.
  • Typical water-soluble polymers for stabilization of vortioxetine and vortioxetine hydrobromide are polyvinyl pyrrolidone (povidone), copovidone, polyvinyl alcohol, hydroxypropyl methylcellulose (hypromellose), hydroxypropyl cellulose, polyethylene glycol, copolymers of polyvinyl caprolactam, polyvinyl acetate - polyethylene glycol (SoluplusTM) etc.
  • Typical water-insoluble polymers for stabilization of vortioxetine and vortioxetine hydrobromide are methylcellulose, ethylcellulose, polymethacrylates, hypromellose, phthalate, hypromellose succinate, hypromellose acetate succinate (HPMCAS), cellulose acetate phthalate, carboxymethyl cellulose etc.
  • An advantage of these polymers is the fact that their solubility is dependent on the pH value of the solution and their use makes it possible to influence releasing of the pharmaceutically active ingredient depending on pH of the alimentary tract.
  • One of the preparation methods of stabilized amorphous forms of vortioxetine and vortioxetine hydrobromide is the dissolution process.
  • the active substance is dissolved in a solvent or in any mixture of solvents.
  • the solvent may be water or any organic solvent.
  • suitable organic solvents one can mention methanol, ethanol, ethyl acetate, isopropyl alcohol, acetone, dichloromethane, tetrahydrofuran etc.
  • a substance stabilizing the active pharmaceutical ingredient is added to this solution or suspension.
  • the solvent is quickly removed and amorphous solid matter results.
  • the solvent can be removed by means of a rotary vacuum evaporator, fluid granulation, spray drying, electrosp inning, solvent freezing etc.
  • This invention is focused on preparation of an amorphous mixture of vortioxetine and vortioxetine hydrobromide with a polymer, which can be used in a pharmaceutical formulation.
  • the following polymers can be advantageously used for the preparation of polymer-stabilized amorphous solid forms of vortioxetine or vortioxetine hydrobromide: polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (Methocel), polymethacrylate derivatives (Eudragit LI 00, Eudragit SlOO) and hypromellose acetate succinate (HPMCAS).
  • polymers in this invention are polyvinyl pyrrolidone (PVP K30) with the molecular, weight of approx. 50,000 Da (g/mol), Methocel E5 with the molecular weight of approx. 22,000 Da (g/mol), Eudragit SlOO with the molecular weight of approx. 125,000 Da (g/mol), Eudragit L100 with the molecular weight of approx. 125,000 Da (g/mol) and hypromellose acetate succinate (HPMCAS-LF).
  • PVP K30 polyvinyl pyrrolidone
  • Methocel E5 with the molecular weight of approx. 22,000 Da (g/mol
  • Eudragit SlOO with the molecular weight of approx. 125,000 Da (g/mol)
  • Eudragit L100 with the molecular weight of approx. 125,000 Da (g/mol)
  • HPMCAS-LF hypromellose acetate succinate
  • the differential scanning calorimetry (DSC) measurement makes it possible to distinguish a solid dispersion and a molecular dispersion, wherein the amorphous solid only exhibits one glass transition value.
  • the prepared amorphous solids in the weight ratio of 1 :2 (API : polymer) formed stable solid dispersions or molecular dispersions whose stability increases with the increasing Tg value (Hancock and Zografi, 1997).
  • the prepared samples were stable in all the cases of storage at 50°C/0 % relative humidity (RH) for the test period of 3 days.
  • RH relative humidity
  • re-crystallization of vortioxetine hydrobromide has been observed when the polymers HPMCAS, PVP K30 and Methocel E5 were used.
  • the samples with the polymers Eudragit LI 00 and Eudragit SI 00 were stable under all the test conditions (see Table 1).
  • Table 1 Stabilities of the prepared amorphous solids of vortioxetine and vortioxetine hydrobromide (weight ratio 1:2), API : polymer)
  • the prepared amorphous solids containing vortioxetine or vortioxetine hydrobromide stabilized with polymers in accordance with this invention can be used for the preparation of pharmaceutical compositions, especially solid dosage forms, e.g. tablets.
  • Such pharmaceutical compositions can contain at least one excipient from the group of fillers (e.g. lactose), binders (e.g. macrocrystalline cellulose), disintegrants (e.g. sodium salt of croscarmellose), lubricants (e.g. magnesium stearate), surfactants etc.
  • These tablets can be coated with common coating compounds, e.g. polyvinyl alcohol or polyethylene glycol.
  • a 10mm mask and a 1/4° fixed anti-dispersion slit were used.
  • the irradiated area of the sample is 10 mm, programmable divergence slits were used.
  • For the correction of the secondary array 0.02 rad Soller slits and a 5.0 anti-dispersion slit were used.
  • the DSC records were measured using a Discovery DSC device made by TA Instruments.
  • the sample charge in a standard Al pot (40 ⁇ ) was between 4-5 mg and the heating rate was 5°C/min.
  • As the carrier gas 5.0 N 2 was used at the flow rate of 50 ml/min.
  • the content of dissolved vortioxetine hydrobromide was analyzed using a UPLC Aquity Waters device.
  • the gradient elution was carried out by mixing of the mobile phase (A), 10 mmol/1 solution of ammonium carbonate in water, pH 10, (B) methanol. Composition of the mobile phase in time, see Table 2:
  • the content was detected using a spectrophotometric measurement at 230 nm. Sample injection volume 1 ⁇ . Injected sample temperature 37°C.
  • the samples were dissolved in plastic Eppendorf tubes having the volume of 2 ml with the use of a shaker (Eppendorf Thermomixer comfort) at 21 Hz and the temperature of 37°C.
  • a shaker Eppendorf Thermomixer comfort
  • the undissolved fraction was removed by means of a centrifuge (Centrifuge MPW-65E) at 14,000 rpm for 5 min and the temperature of 37°C.
  • the resulting product was left to dry in a vacuum drier at the temperature of 40"C and the pressure of 20 kPa for 12 hours.
  • the glass transition temperature of the molecular dispersion according to DSC was 116°C with re-crystallization of the sample at 140°C.
  • the resulting product was left to dry in a vacuum drier at the temperature of 40°C and the pressure of 20 kPa for 12 hours.
  • the glass transition temperature of the molecular dispersion according to DSC was 62°C with re-crystallization of the sample at 140°C (see Fig. 9).
  • the solubility kinetics was studied in an aqueous solution of 0.1 mo 1/1 HC1 with pH 1.2 at 37°C (simulation of conditions in the alimentary tract).
  • the solution was stirred by means of a shaker.
  • the solutions were prepared in such a way that the final concentration could correspond to 1.5 mg/ml.
  • the undissolved solid fraction was removed by centrifugation after 5, 15, 30 and 1440 min.
  • the supernatant was analyzed with reverse-phase HPLC.
  • the concentration of the dissolved vortioxetine hydrobromide was determined based on the peak area of vortioxetine hydrobromide with the use of a calibration line.
  • the calibration series of vortioxetine hydrobromide was in the prepared range of 0.02 - 1.5 mg/1 and in this interval the peak areas exhibited a linear dependence on the concentration.
  • the solubility kinetics of crystalline vortioxetine hydrobromide and the prepared amorphous forms of vortioxetine hydrobromide stabilized by polymers is shown in Fig. 10.
  • a lower content of vortioxetine hydrobromide was measured in the acidic environment after 24 hours than in the case of solubility of the crystalline form.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne un mélange amorphe de vortioxetine de formule I, ou de son sel bromhydrate, avec un polymère, caractérisé en ce que le polymère est choisi parmi des dérivés de polyacrylates, polyméthacrylates, cellulose ou polyvinyles. L'invention concerne également un procédé de préparation dudit mélange amorphe, consistant à dissoudre de la vortioxétine base ou sous forme de sel bromhydrate et un polymère approprié dans un solvant organique adapté, et éliminer ultérieurement le solvant pour produire un mélange amorphe. Un autre procédé consiste à mélanger de la vortioxétine base ou sous forme de sel bromhydrate avec un polymère approprié et chauffer ensuite ce mélange pour obtenir un bain de fusion, puis un mélange amorphe.
PCT/CZ2016/000008 2015-01-21 2016-01-15 Formes amorphes de la vortioxétine stabilisées dans des polymères WO2016116077A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZ2015-31A CZ201531A3 (cs) 2015-01-21 2015-01-21 Polymerem stabilizované amorfní formy vortioxetinu
CZ2015-31 2015-01-21

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3209297A1 (fr) * 2014-10-24 2017-08-30 Hexal Aktiengesellschaft Bromhydrate de vortioxétine amorphe
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
CN113143886A (zh) * 2021-05-07 2021-07-23 苏州康恒研新药物技术有限公司 一种氢溴酸伏硫西汀微丸缓释制剂的制备方法
CN115160258A (zh) * 2022-06-24 2022-10-11 辰欣药业股份有限公司 一种氢溴酸沃替西汀γ晶型的制备方法

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Publication number Priority date Publication date Assignee Title
WO2003029232A1 (fr) 2001-10-04 2003-04-10 H. Lundbeck A/S Derives de phenyl-piperazine en tant qu'inhibiteurs du recaptage de la serotonine
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
WO2014017749A1 (fr) 2012-07-25 2014-01-30 (주)이미지스테크놀로지 Dispositif d'entrée tactile détectant une variation de champ magnétique et une variation de capacité
WO2014170026A1 (fr) * 2013-04-18 2014-10-23 Zentiva, K.S. Ticagrelor amorphe stabilisé
WO2014177491A1 (fr) 2013-04-29 2014-11-06 Lek Pharmaceuticals D.D. Nouvelle forme solide de bromhydrate de 1-(2-((2,4-diméthylphényl)thio)phényl)pipérazine
WO2015044963A1 (fr) * 2013-09-30 2015-04-02 Cadila Healthcare Limited Vortioxétine amorphe et sels de ladite substance
WO2015166379A2 (fr) * 2014-04-28 2015-11-05 Alembic Pharmaceuticals Limited Nouvelles formes polymorphes de la vortioxétine et de ses sels pharmaceutiquement acceptables

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003029232A1 (fr) 2001-10-04 2003-04-10 H. Lundbeck A/S Derives de phenyl-piperazine en tant qu'inhibiteurs du recaptage de la serotonine
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
WO2014017749A1 (fr) 2012-07-25 2014-01-30 (주)이미지스테크놀로지 Dispositif d'entrée tactile détectant une variation de champ magnétique et une variation de capacité
WO2014170026A1 (fr) * 2013-04-18 2014-10-23 Zentiva, K.S. Ticagrelor amorphe stabilisé
WO2014177491A1 (fr) 2013-04-29 2014-11-06 Lek Pharmaceuticals D.D. Nouvelle forme solide de bromhydrate de 1-(2-((2,4-diméthylphényl)thio)phényl)pipérazine
WO2015044963A1 (fr) * 2013-09-30 2015-04-02 Cadila Healthcare Limited Vortioxétine amorphe et sels de ladite substance
WO2015166379A2 (fr) * 2014-04-28 2015-11-05 Alembic Pharmaceuticals Limited Nouvelles formes polymorphes de la vortioxétine et de ses sels pharmaceutiquement acceptables

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3209297A1 (fr) * 2014-10-24 2017-08-30 Hexal Aktiengesellschaft Bromhydrate de vortioxétine amorphe
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
CN113143886A (zh) * 2021-05-07 2021-07-23 苏州康恒研新药物技术有限公司 一种氢溴酸伏硫西汀微丸缓释制剂的制备方法
CN115160258A (zh) * 2022-06-24 2022-10-11 辰欣药业股份有限公司 一种氢溴酸沃替西汀γ晶型的制备方法
CN115160258B (zh) * 2022-06-24 2023-11-17 辰欣药业股份有限公司 一种氢溴酸沃替西汀γ晶型的制备方法

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