WO2020239759A1 - Amorphous enasidenib in a stabilized form - Google Patents

Amorphous enasidenib in a stabilized form Download PDF

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Publication number
WO2020239759A1
WO2020239759A1 PCT/EP2020/064563 EP2020064563W WO2020239759A1 WO 2020239759 A1 WO2020239759 A1 WO 2020239759A1 EP 2020064563 W EP2020064563 W EP 2020064563W WO 2020239759 A1 WO2020239759 A1 WO 2020239759A1
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WIPO (PCT)
Prior art keywords
adsorbate
carrier
enasidenib
enasidenib mesylate
amorphous
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PCT/EP2020/064563
Other languages
French (fr)
Inventor
Verena Adamer
Andrea THALER
Franz Schwarz
Arthur Pichler
Original Assignee
Sandoz Ag
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Publication date
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Publication of WO2020239759A1 publication Critical patent/WO2020239759A1/en

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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
    • A61K9/14—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
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • 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
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the invention relates to an adsorbate comprising amorphous enasidenib mesylate and a solid carrier, wherein the amorphous enasidenib mesylate is preferably present in the carrier in the form of a solid dispersion.
  • the invention also relates to a method of preparing said adsorbate comprising amorphous enasidenib mesylate and a solid carrier. Further, the invention relates to a pharmaceutical formulation and a method for preparing a tablet, wherein both the pharmaceutical formulation and the tablet contain the adsorbate of the present invention.
  • Enasidenib is reported to be an active pharmaceutical agent for the treatment of relapsed or refractory acute myeloid leukemia (AML), preferably in adult patients.
  • AML acute myeloid leukemia
  • enasidenib is used in people with specific mutations of the isocitrate dehydrogenase 2 gene (IDH2-gene). Mutations of the isocitrate dehydrogenase (IDH) can produce (D)-2-hydroxyglutarate (R-2-HG) from a-ketoglutarate, wherein the mutated form of IDH2 catalyses this reaction mainly in mitochondria.
  • (D)-2-hydroxyglutarate can accumulate to very high concentrations, which inhibits the function of enzymes that are dependent on alpha-ketoglutarate. This may lead to a hypermethylated state of DNA and histones, which can contribute to different gene expression that can activate oncogenes and inactivate tumor- suppressor genes and, thus, finally to the growth of tumors
  • Enasidenib is considered to be an allosteric inhibitor of mutant IDH2 enzyme to prevent cell growth and it also has shown to block several other enzymes that play a role in abnormal cell differentiation.
  • enasidenib 2-methyl-l-[(4-[6-(trifluoromethyl)-2- pyridinyl]-6- ⁇ [2-(trifluoromethyl)-4-pyridinyl]amino ⁇ -l,3,5-triazin-2-yl)amino]-2- propanol.
  • the chemical structure of enasidenib is shown in formula (1) below:
  • WO 2015/018060 A1 describes different crystalline forms of 2-methyl-l- [(4-[6-(trifluoromethyl)pyri din-2 -yl]-6- ⁇ [2-(trifluoromethyl)pyri dine-4-yl]amino ⁇ - 1, 3, 5-triazin-2-yl)amino]-2 -propanol methansulfonate, i.e. different polymorphic forms of enasidenib mesylate. These forms can be inter alia obtained by reacting enasidenib and methane sulfonic acid under different conditions with regard to solvent and temperature or converting one form to another by recrystallizing in selected solvents or solvents mixtures.
  • the known polymorphic forms may convert into each other. Such a conversion of polymorphs often results in an unpredictable behaviour of the pharmaceutically active agent with regard to its in vivo and/or in vitro properties such as solubility, bioavailability and stability (shelf-life).
  • enasidenib mesylate in an advantageous form.
  • a form showing advantageous stability e.g. good physical as well as thermal stability, preferably over the whole shelf-life.
  • a solid form of enasidenib mesylate should be provided having a solubility being comparable to crystalline enasidenib mesylate, preferably having a solubility of at least the solubility of crystalline enasidenib mesylate in form 3 of WO 2015/018060.
  • a solid form of enasidenib mesylate should be provided that remains unchanged under granulation and/or tablet compression conditions, thus enabling the provision of dosage forms which comprise a single solid form of enasidenib mesylate. Still further, a solid form should be provided which is advantageous in view of hygroscopicity. Hygroscopic forms often show rather poor shelf-life and are more difficult to handle in a process for producing a pharmaceutical dosage form.
  • an adsorbate comprising amorphous enasidenib mesylate and a solid carrier.
  • a stable amorphous form of enasidenib mesylate can be produced using enasidenib mesylate and a carrier, wherein preferably the amorphous enasidenib mesylate is present in the carrier in the form of a solid dispersion.
  • amorphous enasidenib mesylate according to the present invention is stable under tableting conditions and has at least the solubility of crystalline forms of enasidenib mesylate.
  • enasidenib mesylate has been stabilized in a pure amorphous form without recognizable parts of crystalline enasidenib mesylate.
  • Figures 1 to 7 illustrate a representative X-ray powder diffraction pattern (abbreviated as PXRD or XRPD) of Examples 1.1 to 1.7 according to the present invention.
  • Figure 8 illustrates the PXRD of a Reference Example.
  • the present invention relates to an adsorbate comprising amorphous enasidenib mesylate and a solid carrier, a process of preparing the same, a pharmaceutical composition comprising said adsorbate and a method of preparing tablets comprising the adsorbate.
  • Crystalline substances can be identified experimentally by means of X-ray diffraction, which reveals clearly defined interference patterns for crystalline substances. In contrast to this, X-ray diffraction performed on amorphous substances does not reveal clearly defined interferences for them, but normally only a few diffuse interferences with small diffraction angles.
  • the adsorbate of the invention should contain less than 8% by weight, more preferably less than 3% by weight of enasidenib mesylate with a crystal or crystallite size of more than 500 nm, based on the total weight of the enasidenib mesylate present in the adsorbate. It is further preferred that the adsorbate of the invention contains substantially no crystalline enasidenib mesylate.
  • the adsorbate of the present invention contains less than 8% by weight, more preferably less than 3% by weight of crystalline enasidenib mesylate of any crystal or crystallite size, based on the total weight of the crystalline enasidenib mesylate present in the adsorbate.
  • the crystalline proportion is determined by means of quantitative X-ray diffractometry according to the method of Hermans and Weidinger.
  • the subject of the present invention is an adsorbate comprising amorphous enasidenib mesylate and a solid carrier.
  • adsorbate refers to a pharmaceutical composition comprising the active pharmaceutical ingredient (enasidenib mesylate) and a carrier, wherein said composition can be regarded as "intermediate” and can subsequently be processed in a formulation or oral dosage form.
  • the enasidenib mesylate is adsorbed on and/or in direct contact with the carrier.
  • the amorphous enasidenib mesylate is present in the carrier in the form of a solid dispersion.
  • solid dispersion solution is to be understood in the context of this invention as meaning that enasidenib mesylate is distributed in a molecularly disperse manner on a solid carrier.
  • “molecularly disperse” it is therefore preferable for“molecularly disperse” to be understood as meaning that X-ray diffraction analysis of the enasidenib mesylate contained in the embodiments of the invention does not reveal any clearly defined interference patterns, but at most only a few diffuse interferences with small diffraction angles.
  • the adsorbate of the invention contains preferably less than 5% by weight of enasidenib mesylate particles with a particle size of more than 500 nm, preferably less than 5% by weight of enasidenib mesylate particles with a particle size of more than 300 nm, more preferably less than 5% by weight of enasidenib mesylate particles with a particle size of more than 200 nm, and most preferably less than 5% by weight of enasidenib mesylate particles with a particle size of more than 100 nm.
  • the particle size is determined in this connection by means of confocal Raman spectroscopy.
  • the measuring system preferably consists of an NTEGRA-Spektra Nanofinder ex NT-MDT.
  • the adsorbate of the present invention comprises enasidenib mesylate, preferably molecularly disperse enasidenib mesylate and a carrier.
  • the adsorbate of the invention consists substantially of molecularly disperse enasidenib mesylate, preferably molecularly disperse enasidenib mesylate and a carrier.
  • the expression“substantially” in this case indicates that small amounts of solvent etc. may also be present where applicable.
  • the weight ratio of carrier to enasidenib mesylate can be 20 : 1 to 1 : 2, more preferably 10 : 1 to 1 : 1, even more preferably 6 : 1 to 2 : 1, in particular 5: 1 to 3 : 1.
  • the adsorbate of the present invention comprises solid carrier.
  • a solid carrier is referred to a carrier which is present in a solid form at a pressure of about 101 kPa and a temperature of 23 °C.
  • the carrier is generally a substance for preparing the adsorbate of the present invention, preferably for stabilising enasidenib mesylate in form of a solid dispersion.
  • the carrier can be an organic polymer or an inorganic substance.
  • the carrier is preferably a polymer.
  • the carrier also includes substances which behave like polymers.
  • the carrier also includes solid, non-polymeric compounds which preferably contain polar side groups.
  • the term“carrier” also includes surfactants, especially surfactants which are present in solid form at room temperature.
  • the carrier preferably has a melting point (Ts) or a glass transition temperature of 30°C or more, preferably 30°C to 220°C, more preferably 40°C to 180°C, more preferably 40°C to 100°C. If the carrier is a mixture of substances, it is preferable that each substance in the mixture should have a melting point of 50°C or more.
  • glass transition temperature is used to describe the temperature at which polymers change from the solid state to the liquid state. In the process a distinct change in physical parameters, e.g. hardness and elasticity, occurs. Below the Tg, an excipient or polymer is usually glassy and hard, whereas above the Tg, it changes into a rubber-like to viscous state.
  • the glass transition temperature is determined in the context of this invention by means of dynamic differential scanning calorimetry (DSC).
  • a Mettler Toledo DSC 1 apparatus can be used.
  • the work is performed at a heating rate of l-20°C/min, preferably 10°C/min, and at a cooling rate of 5-25°C/min, preferably 15°C/min.
  • the organic polymer which can be used for the preparation of the adsorbate of the present invention has a number-average molecular weight of 1,000 to 250,000 g/mol, more preferably from 2,000 to 100,000 g/mol and particularly preferably 4,000 to 50,000 g/mol.
  • the resulting solution preferably can have a viscosity of 0.1 to 18 mPaxs, more preferably 0.5 to 15 mPaxs, especially 2 to 8 mPaxs, measured at 25°C. The viscosity is measured here in accordance with the European Pharmacopoeia (Ph. Eur.), 9 th edition, section 2.2.10.
  • Hydrophilic polymers are preferably used for the preparation of the adsorbate. This refers to polymers which possess hydrophilic groups. Examples of suitable hydrophilic groups are hydroxy, alkoxy, acrylate, methacrylate, sulfonate, carboxylate and quaternary ammonium groups. Hydroxy groups are preferable.
  • the adsorbate of the invention may, for example, comprise the following hydrophilic polymers as matrix material: polyvinyl pyrrolidone, polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinyl pyrrolidone/vinyl acetate copolymers (such as Kollidon ® VA64, BASF), polyalkylene glycols, such as polypropylene glycol or preferably polyethylene glycol, co-block polymers of polyethylene glycol, especially co-block polymers of polyethylene glycol and polypropylene glycol (Pluronic ® , BASF), polyethylene oxide, derivatives of methacrylates, polyvinyl alcohol and/polyethylene glycol and mixtures of the polymers men tioned.
  • hydrophilic polymers as matrix material: polyvinyl pyrrolidone, polyvinyl acetate (PVAC), polyvinyl alcohol (PVA
  • the carrier is hydroxypropyl methyl cellulose acetate succinate (HPMC-AS).
  • HPMC-AS having an acetyl content of 10 to 14%, a succinoyl content of 4 to 8%, a methoxy content of 22 to 26% and/or a hydroxypropoxy content of 6 to 10% is used.
  • the carrier also includes solid, non-polymeric compounds which preferably contain polar side groups.
  • these are sugar alcohols or disaccharides.
  • suitable sugar alcohols and/or disaccharides are mannitol, sorbitol, xylitol, isomalt, glucose, fructose, maltose and mixtures thereof.
  • the term“sugar alcohols” in this context also includes monosaccharides.
  • isomalt and sorbitol can be used as carrier material.
  • the matrix material also includes substances which behave like polymers. Examples of these are fats and waxes. It is, for example, possible to use waxes, such as cetyl palmitate, carnauba wax or bees’ wax, as the matrix material. It is likewise possible to use fats, such as glycerol fatty acid esters (e.g. glycerol palmitate, glycerol behenate, glycerol laurate, glycerol stearate), PEG glycerol fatty acid esters or vegetable oils or hydrogenated vegetable oils. Further examples of matrix materials are glycerol, stearyl alcohol, salts of fatty acids.
  • waxes such as cetyl palmitate, carnauba wax or bees’ wax
  • glycerol fatty acid esters e.g. glycerol palmitate, glycerol behenate, glycerol laurate, glycerol stearate
  • natural gum can be used as carrier, e.g. gum traganth, alginates, gum arabic, gum guar.
  • a silicone preferably further mixed with silicon dioxide, such as simethicone, can be used as carrier.
  • the carrier may contain one or more of the above-mentioned substances.
  • the carrier can be an inorganic substance.
  • An inorganic substance can preferably be regarded as a compound that does not contain a hydrocarbon group.
  • inorganic substances suitable to be used as carriers are phosphates, such dicalcium phosphate, amorphous silica such as aerosol and silica gel, clay minerals such as kaolinite, bentonite and montmorillonite, kieselguhr (celite), zeolites, mesoporous silica such as Aeroperl ® 300, MSU-G, MSU-F, MCM-41, MCM-48, SBA-15 and SBA-16, magnesium aluminosilicates such as AI2O3 MgO 1.7Si0 2 xHzO (Neusilin ® ) and aluminosilicates such AL-MCM-41 or mixtures thereof.
  • active coal i.e. activated carbon
  • active coal i.e. activated carbon
  • the carrier in particular the inorganic carrier, has a specific surface area of 50 to 450 m 2 /g, more preferably 75 to 400 m 2 /g, in particular 100 to 300 m 2 /g.
  • the specific surface area preferably is determined by gas adsorption according to Ph. Eur.,9 th edition, Chapter 2.9.26. For this purpose, an ASAP ® 2020 (Micrometries) and an‘outgassing’ temperature of 40°C is used. It has surprisingly been found that the above-mentioned specific surface area might be beneficial for achieving the above-mentioned objects (e.g. formation of the amorphous enasidenib mesylate in a stabilized form).
  • the carrier is a silicate.
  • a silicate as used herein refers to natural or artificial silicate mineral. Further said term includes silicate minerals where aluminium or other tetravalent atoms replace some of the silicon atoms, as in aluminosilicates.
  • the carrier is a magnesium aluminosilicate, especially AI2O3 MgO 1.7Si0 2 xFEO.
  • Neusilin ® is used.
  • silica in particular mesoporous silica.
  • Syloid such as Syloid 72 FP or Syloid Al-1 FP Aeroperl ® 300 is used.
  • the mesoporous silica is in form of pearl-like mesoporous granulates.
  • the granulates can preferably have a mean particle size D50 of 5 to 250 pm, more preferably 10 to 100 pm, even more preferably 15 to 80 pm, in particular 20 to 50 pm
  • the mean particle size can refer to the D50 of the particle size distribution.
  • the average particle size can be determined by means of laser diffractometry.
  • a Malvern Instruments Mastersizer 2000 can be used to determine the size (preferably wet measurement with ultrasound 60 sec., 2,000 rpm, preferably dispersed in sunflower oil, the evaluation being performed according to Particle RI set to 1.520 and Absorption of 2).
  • the mesoporous silica has a specific surface area of 250 to 350 m 2 /g, in particular, 280 to 320 m 2 /g.
  • the volume of the mesoporous silica is 1.0 to 2.5 ml/g, more preferably 1.4 to 1.8 ml/g.
  • Another subject of the invention is a method of preparing an adsorbate comprising amorphous enasidenib mesylate and a solid carrier, comprising the steps of
  • step (a) enasidenib mesylate and the carrier as described above are mixed in a solvent or mixture of solvents.
  • Crystalline or amorphous enasidenib mesylate may be used.
  • crystalline enasidenib mesylate is used.
  • Suitable solvents are, for example, water, alcohol with 1 to 4 carbon atoms (e.g. methanol, ethanol, isopropanol), dimethyl sulfoxide (DMSO), dioxane tetrahydro- furan, acetonitrile, ethyl acetate or mixtures thereof.
  • the boiling point of the solvent is from 40°C to 200°C, more preferably from 50° to 150°C, in particular from 55 to 100°C.
  • methanol is used as solvent.
  • methanol mixed with a different solvent such as one of the above-mentioned solvents which is miscible with methanol can be used.
  • the solvent or the mixture of solvents comprises methanol in an amount of at least 50% v/v, preferably at least 70% v/v, more preferably at least 80% v/v, in particular at least 90% v/v. It is preferred that the solvent is pure methanol.
  • step (a) is preferably carried out under a mechanical treatment such as stirring.
  • mixing can be carried out under ultra-sonification.
  • step (a) is carried out at elevated temperature.
  • An elevated temperature is referred to a temperature above 23°C at about lOlkPa. It is preferred that the elevated temperature is below the boiling temperature of the solvent or the mixture of solvents, more preferable the elevated temperature is from 30°C to the boiling temperature of the solvent or the mixture of solvents minus 10°C.
  • Step (a) is preferably carried out for 5 to 180 minutes, more preferably for 10 to 60 minutes, in particular for about 15 minutes.
  • step (b) the solvent or mixture of solvents is removed, wherein the remaining residue is the adsorbate of the present invention.
  • the solvent can be removed under elevated temperatures and/or preferably under reduced pressure. As far as the elevated temperature is concerned the same applies as described above. In a preferred embodiment the solvent is removed at about 40°C under reduced pressure.
  • the adsorbate of the present invention can be prepared by spray-drying or fluidized bed drying.
  • another subject of the invention is a method of preparing an adsorbate comprising amorphous enasidenib mesylate and a solid carrier, comprising the steps of
  • step (b) spray-drying the suspension from step (a);
  • step (b) spraying the solution from step (a) onto carrier and drying the mixture.
  • Another subject of the invention is an adsorbate obtainable by the method of the present invention.
  • the components as well as the reaction and reaction conditions the same applies as described above.
  • the adsorbate of the invention is usually used as a component in the preparation of a pharmaceutical formulation, in particular in the preparation of a dosage form.
  • another subject of the invention is a pharmaceutical formulation containing enasidenib mesylate in the form of an adsorbate of the invention and optionally at least one further pharmaceutical excipient.
  • the pharmaceutical formulation may be present, for example, in the form of sachets, capsules or tablets. It is also preferable that the pharmaceutical formulations are intended for oral administration, especially for peroral administration.
  • the pharmaceutical formulation might contain just the adsorbate of the present invention, i.e. there might be no need for additional pharmaceutical excipients.
  • said pharmaceutical formulation can comprise at least one additional pharmaceutical excipient, e.g. a glidant.
  • the pharmaceutical formulation is in form of a tablet and it is further preferred that the tablet further comprises one or more pharmaceutically acceptable excipients.
  • the pharmaceutical excipients are excipients with which the person skilled in the art is familiar, such as those which are described in the European Pharmacopoeia. Further, suitable pharmaceutical excipients are for example disclosed in“Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende füre”, published by H.P. Fielder, 4 th Edition, and “Handbook of Pharmaceutical Excipients”, 3 rd Edition, published by A.H. Kibbe, American Pharmaceutical Association, Washington, USA, and Pharmaceutical Press, London.
  • Pharmaceutically acceptable excipient(s) can for example be fillers, disintegrants, glidants and lubricants.
  • the formulation of the invention preferably contains fillers.
  • Fillers generally mean substances which serve to form the body of the tablet in the case of tablets with small amounts of active agent (e.g. less than 70% by weight). This means that fillers “dilute” the active agents in order to produce an adequate tablet- compression mixture. The normal purpose of fillers, therefore, is to obtain a suitable tablet size.
  • Examples of preferred fillers are lactose, lactose derivatives, starch, starch derivatives, microcrystalline cellulose, treated starch, talcum, calcium phosphate, sucrose, calcium carbonate, magnesium carbonate, magnesium oxide, malto- dextrin, calcium sulphate, dextrates, dextrin, dextrose, hydrogenated vegetable oil, kaolin, sodium chloride, and/or potassium chloride.
  • Prosolv ® Rettenmaier & Sohne, Germany
  • Fillers are normally used in an amount of 1 to 99% by weight, more preferably 30 to 95% by weight, based on the total weight of the formulation. In addition, it is, for example, possible for at least 40% by weight or at least 50% by weight filler to be used.
  • Disintegrants are compounds which enhance the ability of the dosage form, preferably the ability of the tablet, to break into smaller fragments when in contact with a liquid, preferably water.
  • the disintegrant can be present in an amount of 0 to 20% by weight, preferably in an amount of 1 to 15% by weight based on the total weight of the pharmaceutical composition.
  • Glidants can be used to improve flowability. Suitable glidants are for example colloidal silicon dioxide, talcum or mixtures thereof.
  • the glidant can be present in an amount of 0 to 8% by weight, preferably in an amount of 0.1 to 3% by weight based on the total weight of the composition.
  • Lubricants generally can be regarded as substances which are suitable to reduce friction, such as static friction, sliding friction and rolling friction.
  • lubricants reduce the shearing forces occurring on the borderline between tablet and mould, especially the sliding friction found during tablet pressing between the punch moving up and down in the die and the die wall on the one hand and between the edge of the tablet and the die wall on the other hand.
  • Lubricants can be for example alkaline earth metal salts of fatty acids, such as magnesium stearate.
  • lubricants can be esters, preferably diesters of glycerol with fatty acids, such as glycerol stearate palmitate.
  • the lubricant can be present for example in an amount of 0 to 5% by weight, preferably in an amount of 0.5 to 2.5% by weight based on the total weight of the composition.
  • the adsorbate of the invention preferably accounts for 5 to 80% by weight of the total weight of the formulation, more preferably 10 to 70% by weight, even more preferably 20 to 60% by weight and especially 45 to 55% by weight. This applies to all the embodiments, irrespective of the nature of the pharmaceutical excipients apart from the adsorbate.
  • the adsorbates of the invention are suitable for serving both as a basis for dosage forms with immediate release (or“if?” for short) and also for those with modified release (or“Mi?” for short).
  • a relatively large amount of disintegrant is used.
  • a relatively small amount of disintegrant is used.
  • the conventional retardation techniques can be used for the MR formulation.
  • the pharmaceutical formulation (both for IR and for MR) preferably contains one or more of the above-mentioned excipients.
  • the examples provided here for the carrier and other excipients are optional, i.e. they may be used in the adsorbates and formulations of the invention but embodiments are of course also encompassed which are free of one or more of the substances or combinations of substances mentioned as examples.
  • the pharmaceutical formulation of the invention is preferably compressed into tablets.
  • Another subject of the invention is a method of preparing a tablet comprising the following steps:
  • step (II) compressing the mixture from step (I) into a tablet.
  • step (I) the adsorbate of the invention and one or more pharmaceutical excipients are mixed.
  • the mixing can be performed in conventional mixers such as Diosna Mixer/Granulator can be preferably carried out until a homogenous mixture is obtained, e.g. for 1 to 180 minutes, more preferably for 3 to 120 minutes, in particular for 5 to 60 minutes. Subsequently, the resulting mixture can be sieved.
  • step (I) the adsorbate of the invention and one or more pharmaceutical excipients can be granulated.
  • a dry -granulation step is carried out.
  • the adsorbate of the present invention is dry granulated with part of the excipients added in step (I) (thus forming an inner phase). Subsequently, the resulting granulates are mixed with the residual excipients (thus forming an outer phase).
  • step (II) the mixture from in step (I) is compressed into tablets, i.e. the step involves compression into tablets.
  • step (I) of the method pharmaceutical excipients may optionally be added to the mixture of step (I).
  • step (II) The amounts of excipients which may be added in step (II) usually depend on the type of tablet to be produced and the amounts of excipients which were already added in step (I). This preferably involves the addition or one or more lubricants, such as those already described above.
  • step (II) can be performed with tableting machines known in the art. Compressing the mixture of step (I) into a tablet can preferably be carried out by compressing said formulation on a rotary press.
  • the main compression force can range from 1 to 50 kN, preferably from 3 to 40 kN.
  • the resulting tablets can have a hardness of 30 to 400 N, more preferably of 50 to 250 N, particularly preferably of 30 to 180 N, more preferably 40 to 150 N, wherein the hardness can be measured according to Ph.Eur. 9.0, Chapter 2.9.8.
  • the tableting conditions are preferably selected such that the resulting tablets have a tablet height to weight ratio of 0.005 to 0.03 mm/mg, more preferably 0.006 to 0.02 mm/mg, particularly preferably 0.007 to 0.015 mm/mg.
  • the resulting tablets preferably have a mass of 50 to 1200 mg, such as 100 to 750 mg, or particularly preferably 120 to 600 mg.
  • the resulting tablets preferably have a hardness of 50 to 300 N, particularly preferably 80 to 250 N. The hardness is determined in accordance with Ph. Eur. 9.0, section 2.9.8.
  • the resulting tablets preferably have a friability of less than 5%, particularly preferably less than 3%, especially less than 2%. The friability is determined in accordance with Ph. Eur. 9.0, section 2.9.7.
  • the tablets of the invention usually exhibit a content uniformity of enasidenib mesylate determined in accordance with Ph. Eur. 9.0, section 2.9.6, which is characterised in that each of ten dosage form units has a content of enasidenib mesylate which lies between 90 and 110%, preferably 95 to 105%, especially 98 to 102% of the average content of those ten dosage form units.
  • the release profile of the tablets of the invention according to the USP method (USP paddle apparatus, 900 ml test medium in phosphate buffer at pH 6.8 and 37° C, 75 rpm) after 30 minutes usually indicates a content released of at least 30%, preferably at least 60%, especially at least 98%.
  • the release profile of the tablets of the invention indicates, for example, a content release of no more than 98%, preferably no more than 90%, further preferably no more than 75%, more preferably no more than 50% and particularly preferably no more than 30%.
  • the above details regarding hardness, friability, content uniformity and release profile preferably relate here to the non-film-coated tablet for an IR formulation.
  • the release profile relates to the total formulation.
  • the tablets produced by the method of the invention are preferably tablets for oral administration and specifically ones which can be swallowed unchewed (non-film- coated or preferably film-coated).
  • macromolecular substances are preferably used, such as modified celluloses, polymethacrylates, polyvinyl pyrrolidone, polyvinyl acetate phthalate, zein and/or shellac or natural gum, such as carrageenan.
  • the amount of the coating is preferably 1 to 10%.
  • a further aspect of the invention is the use of any of the above-mentioned carriers, in particular the use of HPMC-AS, silica and/or magnesium aluminosilicate for stabilizing enasidenib mesylate in amorphous form.
  • HPMC-AS high-MC-AS
  • silica and/or magnesium aluminosilicate for stabilizing enasidenib mesylate in amorphous form.
  • re crystallization of amorphous enasidenib mesylate is inhibited.
  • X-ray powder diffraction was performed with a PANalytical X’Pert PRO diffractometer equipped with a theta/theta coupled goniometer in transmission geometry, Cu-Kalphai , 2 radiation (wavelength 0.15419 nm) with a focusing mirror and a solid state PIXcel detector.
  • the pattern was recorded at a tube voltage of 45 kV and a tube current of 40 mA, applying a step size of 0.013° 2-Theta with 40 s per step (255 channels) in the angular range of 2° to 40° 2-Theta at ambient conditions.
  • a typical precision of the 2-Theta values is in the range of about ⁇ 0.2° 2-Theta.
  • Enasidenib mesylate 250 mg
  • the corresponding amount of carrier were suspended in methanol (50 ml) and stirred at 23°C for about 15 minutes. Subsequently the solvent was removed on a rotavapor with a bath temperature of 40°C under reduced pressure. The resulting product was submitted to PXRD and is shown in Figures 1 to 15.
  • Enasidenib mesylate was dissolved in methanol (50 ml) under stirring. Subsequently the solvent was removed on a rotavapor with a bath temperature of 40°C under reduced pressure as quickly as possible. The resulting product was submitted to PXRD and is shown in Figure 16.
  • the tablet is prepared by forming a granulate having an inner phase and an outer phase.
  • an inner phase comprising enasidenib adsorbates
  • the microcrystalline cellulose, half of the sodium starch glycolate, half of Mg stearate and half of silicon dioxide is prepared (i).
  • the outer phase is formed (ii).
  • the tablet is obtained by tableting the mixture obtained in step (ii) above (inner and outer phases).
  • the composition obtained in step (ii) above is compressed with a Fette® 102i rotary tablet press using a compression force of about 12 to 20 kN (preferably about 16 kN).

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Abstract

The invention relates to an adsorbate comprising amorphous enasidenib mesylate and a solid carrier, wherein the amorphous enasidenib mesylate is preferably present in the carrier in the form of a solid dispersion. The invention also relates to a method of preparing said adsorbate comprising amorphous enasidenib mesylate and a solid carrier. Further, the invention relates to a pharmaceutical formulation and a method for preparing a tablet, wherein both the pharmaceutical formulation and the tablet contain the adsorbate of the present invention.

Description

Amorphous enasidenib in a stabilized form
Technical Field
The invention relates to an adsorbate comprising amorphous enasidenib mesylate and a solid carrier, wherein the amorphous enasidenib mesylate is preferably present in the carrier in the form of a solid dispersion. The invention also relates to a method of preparing said adsorbate comprising amorphous enasidenib mesylate and a solid carrier. Further, the invention relates to a pharmaceutical formulation and a method for preparing a tablet, wherein both the pharmaceutical formulation and the tablet contain the adsorbate of the present invention.
Background
Enasidenib is reported to be an active pharmaceutical agent for the treatment of relapsed or refractory acute myeloid leukemia (AML), preferably in adult patients. In particular, enasidenib is used in people with specific mutations of the isocitrate dehydrogenase 2 gene (IDH2-gene). Mutations of the isocitrate dehydrogenase (IDH) can produce (D)-2-hydroxyglutarate (R-2-HG) from a-ketoglutarate, wherein the mutated form of IDH2 catalyses this reaction mainly in mitochondria. Thus, (D)-2-hydroxyglutarate can accumulate to very high concentrations, which inhibits the function of enzymes that are dependent on alpha-ketoglutarate. This may lead to a hypermethylated state of DNA and histones, which can contribute to different gene expression that can activate oncogenes and inactivate tumor- suppressor genes and, thus, finally to the growth of tumors.
Enasidenib is considered to be an allosteric inhibitor of mutant IDH2 enzyme to prevent cell growth and it also has shown to block several other enzymes that play a role in abnormal cell differentiation.
The IUPAC name of enasidenib is 2-methyl-l-[(4-[6-(trifluoromethyl)-2- pyridinyl]-6-{[2-(trifluoromethyl)-4-pyridinyl]amino}-l,3,5-triazin-2-yl)amino]-2- propanol. The chemical structure of enasidenib is shown in formula (1) below:
Figure imgf000003_0001
The synthesis of enasidenib and salts thereof is described in, for example, WO 2013/102431 A1 (compound 409).
Further, WO 2015/018060 A1 describes different crystalline forms of 2-methyl-l- [(4-[6-(trifluoromethyl)pyri din-2 -yl]-6-{ [2-(trifluoromethyl)pyri dine-4-yl]amino} - 1, 3, 5-triazin-2-yl)amino]-2 -propanol methansulfonate, i.e. different polymorphic forms of enasidenib mesylate. These forms can be inter alia obtained by reacting enasidenib and methane sulfonic acid under different conditions with regard to solvent and temperature or converting one form to another by recrystallizing in selected solvents or solvents mixtures.
All in all, the prior art forms show certain drawbacks which render their use rather challenging for pharmaceutical purposes. For example, the known polymorphic forms may convert into each other. Such a conversion of polymorphs often results in an unpredictable behaviour of the pharmaceutically active agent with regard to its in vivo and/or in vitro properties such as solubility, bioavailability and stability (shelf-life).
It was found that due to the low solubility of enasidenib mesylate in most solvents, the preparation of amorphous enasidenib mesylate is difficult. Additionally, the amorphous form of enasidenib mesylate tends to be physically unstable since it is prone to convert into one or more crystalline forms under various humidity and temperature conditions. In fact, the amorphous form of enasidenib mesylate is reported to at least partially crystallize spontaneously at 23°C, 101,325 kPa and 40% rh. For example, dissolving enasidenib mesylate in methanol and removing the solvent, for example by means of a rotavapor, scarcely leads to pure amorphous enasidenib mesylate, in most cases enasidenib mesylate partially crystallizes. Another way for the preparation of amorphous compounds is milling, for example in a ball mill. However, to break up the crystalline structure of amounts of enasidenib mesylate in lab scale requires very harsh conditions, for example milling at 30 Hertz for several hours. As a result, the temperature increases significantly, and the compound becomes prone to chemical degradation. In view of this, this kind of an amorphization process is not scalable and thus not economically practicable.
Thus, it was an object of the invention to overcome the drawbacks of the prior art and to provide enasidenib mesylate in an advantageous form. In particular a form showing advantageous stability, e.g. good physical as well as thermal stability, preferably over the whole shelf-life. Further, a solid form of enasidenib mesylate should be provided having a solubility being comparable to crystalline enasidenib mesylate, preferably having a solubility of at least the solubility of crystalline enasidenib mesylate in form 3 of WO 2015/018060. Moreover, a solid form of enasidenib mesylate should be provided that remains unchanged under granulation and/or tablet compression conditions, thus enabling the provision of dosage forms which comprise a single solid form of enasidenib mesylate. Still further, a solid form should be provided which is advantageous in view of hygroscopicity. Hygroscopic forms often show rather poor shelf-life and are more difficult to handle in a process for producing a pharmaceutical dosage form.
It is further an object of the present invention to provide a process for the preparation of such a form of enasidenib mesylate.
Summary of the invention
The above objectives are unexpectedly achieved by the provision of an adsorbate comprising amorphous enasidenib mesylate and a solid carrier. In particular, it has been surprisingly found that a stable amorphous form of enasidenib mesylate can be produced using enasidenib mesylate and a carrier, wherein preferably the amorphous enasidenib mesylate is present in the carrier in the form of a solid dispersion. Further, amorphous enasidenib mesylate according to the present invention is stable under tableting conditions and has at least the solubility of crystalline forms of enasidenib mesylate. Moreover, enasidenib mesylate has been stabilized in a pure amorphous form without recognizable parts of crystalline enasidenib mesylate.
Brief description of the drawings
Figures 1 to 7 illustrate a representative X-ray powder diffraction pattern (abbreviated as PXRD or XRPD) of Examples 1.1 to 1.7 according to the present invention.
Figure 8 illustrates the PXRD of a Reference Example.
Detailed description of the invention
The present invention relates to an adsorbate comprising amorphous enasidenib mesylate and a solid carrier, a process of preparing the same, a pharmaceutical composition comprising said adsorbate and a method of preparing tablets comprising the adsorbate.
The term“crystalline” can be used in the context of this invention to designate the state of solid substances in which the components (atoms, ions or molecules) are arranged in an orderly repeating pattern, extending in all three spatial dimensions and thus exhibit a periodic arrangement over a great range (= long-range order). Crystals are thus anisotropic. Crystalline substances can be identified experimentally by means of X-ray diffraction, which reveals clearly defined interference patterns for crystalline substances. In contrast to this, X-ray diffraction performed on amorphous substances does not reveal clearly defined interferences for them, but normally only a few diffuse interferences with small diffraction angles.
The term“amorphous” can be used in the context of this invention to designate the state of solid substances in which the components (atoms, ions or molecules) do not exhibit any periodic arrangement over a great range (= long-range order). In amorphous substances, the components are usually not arranged in a totally disordered fashion and completely randomly but are rather distributed in such a way that a certain regularity and similarity to the crystalline state can be observed with regard to the distance from and orientation towards their closest neighbours (= short-range order). Consequently, amorphous substances preferably possess a short-range order but no long-range order.
It is preferable that the adsorbate of the invention should contain less than 8% by weight, more preferably less than 3% by weight of enasidenib mesylate with a crystal or crystallite size of more than 500 nm, based on the total weight of the enasidenib mesylate present in the adsorbate. It is further preferred that the adsorbate of the invention contains substantially no crystalline enasidenib mesylate. In particular, the adsorbate of the present invention contains less than 8% by weight, more preferably less than 3% by weight of crystalline enasidenib mesylate of any crystal or crystallite size, based on the total weight of the crystalline enasidenib mesylate present in the adsorbate. The crystalline proportion is determined by means of quantitative X-ray diffractometry according to the method of Hermans and Weidinger.
Thus, the subject of the present invention is an adsorbate comprising amorphous enasidenib mesylate and a solid carrier.
The term "adsorbate" as used herein refers to a pharmaceutical composition comprising the active pharmaceutical ingredient (enasidenib mesylate) and a carrier, wherein said composition can be regarded as "intermediate" and can subsequently be processed in a formulation or oral dosage form. Preferably the enasidenib mesylate is adsorbed on and/or in direct contact with the carrier.
In a preferred embodiment of the invention the amorphous enasidenib mesylate is present in the carrier in the form of a solid dispersion.
The term“solid dispersion solution” is to be understood in the context of this invention as meaning that enasidenib mesylate is distributed in a molecularly disperse manner on a solid carrier.
It is therefore preferable for“molecularly disperse” to be understood as meaning that X-ray diffraction analysis of the enasidenib mesylate contained in the embodiments of the invention does not reveal any clearly defined interference patterns, but at most only a few diffuse interferences with small diffraction angles.
It is also preferable for“molecularly disperse” to be understood as meaning that the adsorbate of the invention contains preferably less than 5% by weight of enasidenib mesylate particles with a particle size of more than 500 nm, preferably less than 5% by weight of enasidenib mesylate particles with a particle size of more than 300 nm, more preferably less than 5% by weight of enasidenib mesylate particles with a particle size of more than 200 nm, and most preferably less than 5% by weight of enasidenib mesylate particles with a particle size of more than 100 nm.
The particle size is determined in this connection by means of confocal Raman spectroscopy. The measuring system preferably consists of an NTEGRA-Spektra Nanofinder ex NT-MDT.
In the context of this invention, the adsorbate of the present invention comprises enasidenib mesylate, preferably molecularly disperse enasidenib mesylate and a carrier. In particular, the adsorbate of the invention consists substantially of molecularly disperse enasidenib mesylate, preferably molecularly disperse enasidenib mesylate and a carrier. The expression“substantially” in this case indicates that small amounts of solvent etc. may also be present where applicable.
In a preferred embodiment of the invention there is a weight excess of carrier compared to enasidenib mesylate. In particular, the weight ratio of carrier to enasidenib mesylate can be 20 : 1 to 1 : 2, more preferably 10 : 1 to 1 : 1, even more preferably 6 : 1 to 2 : 1, in particular 5: 1 to 3 : 1.
Apart from enasidenib mesylate the adsorbate of the present invention comprises solid carrier. A solid carrier is referred to a carrier which is present in a solid form at a pressure of about 101 kPa and a temperature of 23 °C.
The carrier is generally a substance for preparing the adsorbate of the present invention, preferably for stabilising enasidenib mesylate in form of a solid dispersion.
In a preferred embodiment of the present invention the carrier can be an organic polymer or an inorganic substance.
The carrier is preferably a polymer. In addition, the carrier also includes substances which behave like polymers. Furthermore, the carrier also includes solid, non-polymeric compounds which preferably contain polar side groups. Finally, the term“carrier” also includes surfactants, especially surfactants which are present in solid form at room temperature. The carrier preferably has a melting point (Ts) or a glass transition temperature of 30°C or more, preferably 30°C to 220°C, more preferably 40°C to 180°C, more preferably 40°C to 100°C. If the carrier is a mixture of substances, it is preferable that each substance in the mixture should have a melting point of 50°C or more.
The term“glass transition temperature” (Tg) is used to describe the temperature at which polymers change from the solid state to the liquid state. In the process a distinct change in physical parameters, e.g. hardness and elasticity, occurs. Below the Tg, an excipient or polymer is usually glassy and hard, whereas above the Tg, it changes into a rubber-like to viscous state. The glass transition temperature is determined in the context of this invention by means of dynamic differential scanning calorimetry (DSC).
For this purpose, a Mettler Toledo DSC 1 apparatus can be used. The work is performed at a heating rate of l-20°C/min, preferably 10°C/min, and at a cooling rate of 5-25°C/min, preferably 15°C/min.
In addition, the organic polymer which can be used for the preparation of the adsorbate of the present invention has a number-average molecular weight of 1,000 to 250,000 g/mol, more preferably from 2,000 to 100,000 g/mol and particularly preferably 4,000 to 50,000 g/mol. When the polymer used in the preparation of the adsorbate is dissolved in (distilled) water in an amount of 2% by weight, the resulting solution preferably can have a viscosity of 0.1 to 18 mPaxs, more preferably 0.5 to 15 mPaxs, especially 2 to 8 mPaxs, measured at 25°C. The viscosity is measured here in accordance with the European Pharmacopoeia (Ph. Eur.), 9th edition, section 2.2.10.
Hydrophilic polymers are preferably used for the preparation of the adsorbate. This refers to polymers which possess hydrophilic groups. Examples of suitable hydrophilic groups are hydroxy, alkoxy, acrylate, methacrylate, sulfonate, carboxylate and quaternary ammonium groups. Hydroxy groups are preferable.
The adsorbate of the invention may, for example, comprise the following hydrophilic polymers as matrix material: polyvinyl pyrrolidone, polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinyl pyrrolidone/vinyl acetate copolymers (such as Kollidon® VA64, BASF), polyalkylene glycols, such as polypropylene glycol or preferably polyethylene glycol, co-block polymers of polyethylene glycol, especially co-block polymers of polyethylene glycol and polypropylene glycol (Pluronic®, BASF), polyethylene oxide, derivatives of methacrylates, polyvinyl alcohol and/polyethylene glycol and mixtures of the polymers men tioned.
In a more preferred embodiment the carrier is hydroxypropyl methyl cellulose acetate succinate (HPMC-AS). In a preferred embodiment HPMC-AS having an acetyl content of 10 to 14%, a succinoyl content of 4 to 8%, a methoxy content of 22 to 26% and/or a hydroxypropoxy content of 6 to 10% is used.
Furthermore, the carrier also includes solid, non-polymeric compounds which preferably contain polar side groups. Examples of these are sugar alcohols or disaccharides. Examples of suitable sugar alcohols and/or disaccharides are mannitol, sorbitol, xylitol, isomalt, glucose, fructose, maltose and mixtures thereof. The term“sugar alcohols” in this context also includes monosaccharides. In particular, isomalt and sorbitol can be used as carrier material.
In addition, the matrix material also includes substances which behave like polymers. Examples of these are fats and waxes. It is, for example, possible to use waxes, such as cetyl palmitate, carnauba wax or bees’ wax, as the matrix material. It is likewise possible to use fats, such as glycerol fatty acid esters (e.g. glycerol palmitate, glycerol behenate, glycerol laurate, glycerol stearate), PEG glycerol fatty acid esters or vegetable oils or hydrogenated vegetable oils. Further examples of matrix materials are glycerol, stearyl alcohol, salts of fatty acids.
Apart from that, natural gum can be used as carrier, e.g. gum traganth, alginates, gum arabic, gum guar.
Alternatively, also a silicone, preferably further mixed with silicon dioxide, such as simethicone, can be used as carrier.
The carrier may contain one or more of the above-mentioned substances. In a more preferred embodiment of the invention the carrier can be an inorganic substance. An inorganic substance can preferably be regarded as a compound that does not contain a hydrocarbon group.
Examples for inorganic substances suitable to be used as carriers are phosphates, such dicalcium phosphate, amorphous silica such as aerosol and silica gel, clay minerals such as kaolinite, bentonite and montmorillonite, kieselguhr (celite), zeolites, mesoporous silica such as Aeroperl® 300, MSU-G, MSU-F, MCM-41, MCM-48, SBA-15 and SBA-16, magnesium aluminosilicates such as AI2O3 MgO 1.7Si02 xHzO (Neusilin®) and aluminosilicates such AL-MCM-41 or mixtures thereof. Further, active coal (i.e. activated carbon) can be preferably used as carrier.
In a preferred embodiment the carrier, in particular the inorganic carrier, has a specific surface area of 50 to 450 m2/g, more preferably 75 to 400 m2/g, in particular 100 to 300 m2/g. The specific surface area preferably is determined by gas adsorption according to Ph. Eur.,9th edition, Chapter 2.9.26. For this purpose, an ASAP® 2020 (Micrometries) and an‘outgassing’ temperature of 40°C is used. It has surprisingly been found that the above-mentioned specific surface area might be beneficial for achieving the above-mentioned objects (e.g. formation of the amorphous enasidenib mesylate in a stabilized form).
In a preferred embodiment the carrier is a silicate. A silicate as used herein refers to natural or artificial silicate mineral. Further said term includes silicate minerals where aluminium or other tetravalent atoms replace some of the silicon atoms, as in aluminosilicates.
Preferably, the carrier is a magnesium aluminosilicate, especially AI2O3 MgO 1.7Si02 xFEO. In an alternative particularly preferred embodiment Neusilin® is used. Alternatively preferred as carrier is silica, in particular mesoporous silica. In a particularly preferred embodiment Syloid such as Syloid 72 FP or Syloid Al-1 FP Aeroperl® 300 is used.
It is further preferred that the mesoporous silica is in form of pearl-like mesoporous granulates. The granulates can preferably have a mean particle size D50 of 5 to 250 pm, more preferably 10 to 100 pm, even more preferably 15 to 80 pm, in particular 20 to 50 pm
The mean particle size can refer to the D50 of the particle size distribution. The average particle size can be determined by means of laser diffractometry. In particular, a Malvern Instruments Mastersizer 2000 can be used to determine the size (preferably wet measurement with ultrasound 60 sec., 2,000 rpm, preferably dispersed in sunflower oil, the evaluation being performed according to Particle RI set to 1.520 and Absorption of 2).
Preferably, the mesoporous silica has a specific surface area of 250 to 350 m2/g, in particular, 280 to 320 m2/g. Preferably, the volume of the mesoporous silica is 1.0 to 2.5 ml/g, more preferably 1.4 to 1.8 ml/g.
Another subject of the invention is a method of preparing an adsorbate comprising amorphous enasidenib mesylate and a solid carrier, comprising the steps of
(a) mixing enasidenib mesylate and the carrier in a solvent or mixture of solvents, and
(b) removing the solvent or mixture of solvents.
In step (a), enasidenib mesylate and the carrier as described above are mixed in a solvent or mixture of solvents. Crystalline or amorphous enasidenib mesylate may be used. Preferably, crystalline enasidenib mesylate is used. Suitable solvents are, for example, water, alcohol with 1 to 4 carbon atoms (e.g. methanol, ethanol, isopropanol), dimethyl sulfoxide (DMSO), dioxane tetrahydro- furan, acetonitrile, ethyl acetate or mixtures thereof.
It is preferred that the boiling point of the solvent is from 40°C to 200°C, more preferably from 50° to 150°C, in particular from 55 to 100°C.
Preferably methanol is used as solvent. Alternatively, methanol mixed with a different solvent, such as one of the above-mentioned solvents which is miscible with methanol can be used.
In a preferred embodiment the solvent or the mixture of solvents comprises methanol in an amount of at least 50% v/v, preferably at least 70% v/v, more preferably at least 80% v/v, in particular at least 90% v/v. It is preferred that the solvent is pure methanol.
The mixing in step (a) is preferably carried out under a mechanical treatment such as stirring. Alternatively mixing can be carried out under ultra-sonification.
In a preferred embodiment step (a) is carried out at elevated temperature. An elevated temperature is referred to a temperature above 23°C at about lOlkPa. It is preferred that the elevated temperature is below the boiling temperature of the solvent or the mixture of solvents, more preferable the elevated temperature is from 30°C to the boiling temperature of the solvent or the mixture of solvents minus 10°C.
Step (a) is preferably carried out for 5 to 180 minutes, more preferably for 10 to 60 minutes, in particular for about 15 minutes.
In step (b) the solvent or mixture of solvents is removed, wherein the remaining residue is the adsorbate of the present invention. The solvent can be removed under elevated temperatures and/or preferably under reduced pressure. As far as the elevated temperature is concerned the same applies as described above. In a preferred embodiment the solvent is removed at about 40°C under reduced pressure.
In an alternative embodiment the adsorbate of the present invention can be prepared by spray-drying or fluidized bed drying. Hence, another subject of the invention is a method of preparing an adsorbate comprising amorphous enasidenib mesylate and a solid carrier, comprising the steps of
(a) providing a suspension comprising enasidenib mesylate dissolved in solvent or mixture of solvents and carrier, and
(b) spray-drying the suspension from step (a); or
(a) dissolving enasidenib mesylate in a solvent or mixture of solvents, and
(b) spraying the solution from step (a) onto carrier and drying the mixture.
Another subject of the invention is an adsorbate obtainable by the method of the present invention. With regard to the components as well as the reaction and reaction conditions the same applies as described above.
The adsorbate of the invention is usually used as a component in the preparation of a pharmaceutical formulation, in particular in the preparation of a dosage form.
Thus, another subject of the invention is a pharmaceutical formulation containing enasidenib mesylate in the form of an adsorbate of the invention and optionally at least one further pharmaceutical excipient.
The pharmaceutical formulation may be present, for example, in the form of sachets, capsules or tablets. It is also preferable that the pharmaceutical formulations are intended for oral administration, especially for peroral administration. In case that the pharmaceutical formulation is present in form of a sachet or a capsule, preferably a capsule, the pharmaceutical formulation might contain just the adsorbate of the present invention, i.e. there might be no need for additional pharmaceutical excipients. Preferably, said pharmaceutical formulation can comprise at least one additional pharmaceutical excipient, e.g. a glidant.
It is preferred that the pharmaceutical formulation is in form of a tablet and it is further preferred that the tablet further comprises one or more pharmaceutically acceptable excipients.
The pharmaceutical excipients are excipients with which the person skilled in the art is familiar, such as those which are described in the European Pharmacopoeia. Further, suitable pharmaceutical excipients are for example disclosed in“Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete”, published by H.P. Fielder, 4th Edition, and “Handbook of Pharmaceutical Excipients”, 3rd Edition, published by A.H. Kibbe, American Pharmaceutical Association, Washington, USA, and Pharmaceutical Press, London.
Pharmaceutically acceptable excipient(s) can for example be fillers, disintegrants, glidants and lubricants.
The formulation of the invention preferably contains fillers. “Fillers” generally mean substances which serve to form the body of the tablet in the case of tablets with small amounts of active agent (e.g. less than 70% by weight). This means that fillers “dilute” the active agents in order to produce an adequate tablet- compression mixture. The normal purpose of fillers, therefore, is to obtain a suitable tablet size.
Examples of preferred fillers are lactose, lactose derivatives, starch, starch derivatives, microcrystalline cellulose, treated starch, talcum, calcium phosphate, sucrose, calcium carbonate, magnesium carbonate, magnesium oxide, malto- dextrin, calcium sulphate, dextrates, dextrin, dextrose, hydrogenated vegetable oil, kaolin, sodium chloride, and/or potassium chloride. Prosolv® (Rettenmaier & Sohne, Germany) can likewise be used.
Fillers are normally used in an amount of 1 to 99% by weight, more preferably 30 to 95% by weight, based on the total weight of the formulation. In addition, it is, for example, possible for at least 40% by weight or at least 50% by weight filler to be used.
Disintegrants are compounds which enhance the ability of the dosage form, preferably the ability of the tablet, to break into smaller fragments when in contact with a liquid, preferably water. Suitable disintegrants are for example croscar- mellose sodium, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone (crospovidone), sodium carboxymethylglycolate (= sodium starch glycolate) and sodium bicarbonate, preferably cross-linked polyvinylpyrrolidone (crospovidone) and sodium carboxymethylglycolate. The disintegrant can be present in an amount of 0 to 20% by weight, preferably in an amount of 1 to 15% by weight based on the total weight of the pharmaceutical composition.
Glidants can be used to improve flowability. Suitable glidants are for example colloidal silicon dioxide, talcum or mixtures thereof. The glidant can be present in an amount of 0 to 8% by weight, preferably in an amount of 0.1 to 3% by weight based on the total weight of the composition.
Lubricants generally can be regarded as substances which are suitable to reduce friction, such as static friction, sliding friction and rolling friction. In particular, lubricants reduce the shearing forces occurring on the borderline between tablet and mould, especially the sliding friction found during tablet pressing between the punch moving up and down in the die and the die wall on the one hand and between the edge of the tablet and the die wall on the other hand. Lubricants can be for example alkaline earth metal salts of fatty acids, such as magnesium stearate. Alternatively, lubricants can be esters, preferably diesters of glycerol with fatty acids, such as glycerol stearate palmitate. The lubricant can be present for example in an amount of 0 to 5% by weight, preferably in an amount of 0.5 to 2.5% by weight based on the total weight of the composition.
The adsorbate of the invention preferably accounts for 5 to 80% by weight of the total weight of the formulation, more preferably 10 to 70% by weight, even more preferably 20 to 60% by weight and especially 45 to 55% by weight. This applies to all the embodiments, irrespective of the nature of the pharmaceutical excipients apart from the adsorbate.
In a preferred embodiment the pharmaceutical formulation of the present invention comprises
5 to 50% by weight, preferably 20 to 30% by weight enasidenib mesylate,
5 to 50% by weight, preferably 20 to 30% by weight solid carrier,
10 to 80% by weight, preferably 45 to 55% by weight filler,
1 to 10% by weight, preferably 3 to 5% by weight disintegrant,
0.2 to 5% by weight, preferably 0.5 to 2% by weight glidant, and
0.2 to 5% by weight, preferably 0.5 to 2% by weight lubricant.
It has been shown that the adsorbates of the invention are suitable for serving both as a basis for dosage forms with immediate release (or“if?” for short) and also for those with modified release (or“Mi?” for short).
In a preferred embodiment for an IR formulation, a relatively large amount of disintegrant is used.
In a preferred embodiment for an MR formulation, a relatively small amount of disintegrant is used. In addition, the conventional retardation techniques can be used for the MR formulation.
Furthermore, the pharmaceutical formulation (both for IR and for MR) preferably contains one or more of the above-mentioned excipients. The examples provided here for the carrier and other excipients are optional, i.e. they may be used in the adsorbates and formulations of the invention but embodiments are of course also encompassed which are free of one or more of the substances or combinations of substances mentioned as examples.
The pharmaceutical formulation of the invention is preferably compressed into tablets.
Thus, another subject of the invention is a method of preparing a tablet comprising the following steps:
(I) mixing and/or granulating the adsorbate of the invention and one or more pharmaceutical excipients;
(II) compressing the mixture from step (I) into a tablet.
In step (I) the adsorbate of the invention and one or more pharmaceutical excipients are mixed. As far as the adsorbate and the pharmaceutical excipients are concerned the same applies as described above. The mixing can be performed in conventional mixers such as Diosna Mixer/Granulator can be preferably carried out until a homogenous mixture is obtained, e.g. for 1 to 180 minutes, more preferably for 3 to 120 minutes, in particular for 5 to 60 minutes. Subsequently, the resulting mixture can be sieved.
Further, in step (I) the adsorbate of the invention and one or more pharmaceutical excipients can be granulated. Preferably a dry -granulation step is carried out.
In a preferred embodiment the adsorbate of the present invention is dry granulated with part of the excipients added in step (I) (thus forming an inner phase). Subsequently, the resulting granulates are mixed with the residual excipients (thus forming an outer phase). In step (II) the mixture from in step (I) is compressed into tablets, i.e. the step involves compression into tablets.
In step (I) of the method, pharmaceutical excipients may optionally be added to the mixture of step (I).
The amounts of excipients which may be added in step (II) usually depend on the type of tablet to be produced and the amounts of excipients which were already added in step (I). This preferably involves the addition or one or more lubricants, such as those already described above.
Compression in step (II) can be performed with tableting machines known in the art. Compressing the mixture of step (I) into a tablet can preferably be carried out by compressing said formulation on a rotary press. The main compression force can range from 1 to 50 kN, preferably from 3 to 40 kN. The resulting tablets can have a hardness of 30 to 400 N, more preferably of 50 to 250 N, particularly preferably of 30 to 180 N, more preferably 40 to 150 N, wherein the hardness can be measured according to Ph.Eur. 9.0, Chapter 2.9.8.
The tableting conditions are preferably selected such that the resulting tablets have a tablet height to weight ratio of 0.005 to 0.03 mm/mg, more preferably 0.006 to 0.02 mm/mg, particularly preferably 0.007 to 0.015 mm/mg.
In accordance with the invention, the resulting tablets preferably have a mass of 50 to 1200 mg, such as 100 to 750 mg, or particularly preferably 120 to 600 mg.
In addition, the resulting tablets preferably have a hardness of 50 to 300 N, particularly preferably 80 to 250 N. The hardness is determined in accordance with Ph. Eur. 9.0, section 2.9.8. In addition, the resulting tablets preferably have a friability of less than 5%, particularly preferably less than 3%, especially less than 2%. The friability is determined in accordance with Ph. Eur. 9.0, section 2.9.7.
Finally, the tablets of the invention usually exhibit a content uniformity of enasidenib mesylate determined in accordance with Ph. Eur. 9.0, section 2.9.6, which is characterised in that each of ten dosage form units has a content of enasidenib mesylate which lies between 90 and 110%, preferably 95 to 105%, especially 98 to 102% of the average content of those ten dosage form units.
In the case of an IR formulation, the release profile of the tablets of the invention according to the USP method (USP paddle apparatus, 900 ml test medium in phosphate buffer at pH 6.8 and 37° C, 75 rpm) after 30 minutes usually indicates a content released of at least 30%, preferably at least 60%, especially at least 98%.
In the case of an MR formulation, the release profile of the tablets of the invention (USP paddle apparatus, 900 ml test medium in phosphate buffer at pH 6.8 and 37°C, 75 rpm) after 10 minutes indicates, for example, a content release of no more than 98%, preferably no more than 90%, further preferably no more than 75%, more preferably no more than 50% and particularly preferably no more than 30%.
The above details regarding hardness, friability, content uniformity and release profile preferably relate here to the non-film-coated tablet for an IR formulation. For a modified-release tablet, the release profile relates to the total formulation.
The tablets produced by the method of the invention are preferably tablets for oral administration and specifically ones which can be swallowed unchewed (non-film- coated or preferably film-coated).
In the case of tablets which are swallowed unchewed it is preferable that they be coated with a film layer. For this purpose, the methods of film-coating tablets which are standard in the art may be employed. The above-mentioned ratios of active agent to excipient, however, relate to the non-film-coated tablet.
For film-coating, macromolecular substances are preferably used, such as modified celluloses, polymethacrylates, polyvinyl pyrrolidone, polyvinyl acetate phthalate, zein and/or shellac or natural gum, such as carrageenan.
The amount of the coating is preferably 1 to 10%.
A further aspect of the invention is the use of any of the above-mentioned carriers, in particular the use of HPMC-AS, silica and/or magnesium aluminosilicate for stabilizing enasidenib mesylate in amorphous form. In a preferred embodiment re crystallization of amorphous enasidenib mesylate is inhibited.
The following non-limiting examples are illustrative for the disclosure.
Experimental part
Analytical Methods
XRPD:
X-ray powder diffraction (XRPD) was performed with a PANalytical X’Pert PRO diffractometer equipped with a theta/theta coupled goniometer in transmission geometry, Cu-Kalphai, 2 radiation (wavelength 0.15419 nm) with a focusing mirror and a solid state PIXcel detector. The pattern was recorded at a tube voltage of 45 kV and a tube current of 40 mA, applying a step size of 0.013° 2-Theta with 40 s per step (255 channels) in the angular range of 2° to 40° 2-Theta at ambient conditions. A typical precision of the 2-Theta values is in the range of about ± 0.2° 2-Theta. Preparation of adsorbates comprising enasidenib mesylate and carrier
General procedure:
Enasidenib mesylate (250 mg) and the corresponding amount of carrier were suspended in methanol (50 ml) and stirred at 23°C for about 15 minutes. Subsequently the solvent was removed on a rotavapor with a bath temperature of 40°C under reduced pressure. The resulting product was submitted to PXRD and is shown in Figures 1 to 15.
Reference Example:
Enasidenib mesylate was dissolved in methanol (50 ml) under stirring. Subsequently the solvent was removed on a rotavapor with a bath temperature of 40°C under reduced pressure as quickly as possible. The resulting product was submitted to PXRD and is shown in Figure 16.
Figure imgf000022_0001
As can be seen the PXRD of present Examples 1.1 to 1.7 show an amorphous enasidenib without crystalline parts, while in the Reference Example crystalline parts can be detected. Preparation of filmcoated tablets:
General procedure:
The tablet is prepared by forming a granulate having an inner phase and an outer phase. By dry granulating an inner phase comprising enasidenib adsorbates, the microcrystalline cellulose, half of the sodium starch glycolate, half of Mg stearate and half of silicon dioxide is prepared (i). Then by blending the resulting granules with the sieved second half of sodium starch glycol, the second half of Mg stearate and the second half of silicon dioxide the outer phase is formed (ii).
The tablet is obtained by tableting the mixture obtained in step (ii) above (inner and outer phases). The composition obtained in step (ii) above is compressed with a Fette® 102i rotary tablet press using a compression force of about 12 to 20 kN (preferably about 16 kN).
Reference example (mg/tablet 100 mg active):
Enasidenib mesylate/Syloid 72 FP adsorbate 240
Microcrystalline cellulose 240
Sodium starch glycolate 10
Silicon dioxide 5
Mg stearate 5
Total core weight 500

Claims

Claims
1. An adsorbate comprising amorphous enasidenib mesylate and a solid carrier.
2. The adsorbate according to claim 1, wherein the amorphous enasidenib mesylate is present in the carrier in the form of a solid dispersion.
3. The adsorbate according to claim 1 or 2, wherein the weight ratio of carrier to enasidenib mesylate is 10 : 1 to 1 : 1.
4. The adsorbate according to any one of claims 1 to 3, wherein the carrier is an organic polymer or an inorganic substance.
5. The adsorbate according to any one of claims 1 to 4, wherein the carrier is HPMC-AS.
6. The adsorbate according to any one of claims 1 to 4, wherein the carrier is a magnesium aluminosilicate or mesoporous silica.
7. The adsorbate according to any one of claims 1 to 6, wherein the carrier possesses a specific surface area of 75 to 350 m2/g, whereby the specific surface area is measured according to Ph.Eur. 9.0, 2.9.26.
8. A method of preparing an adsorbate comprising amorphous enasidenib mesylate and a solid carrier comprising the steps of
(a) mixing enasidenib mesylate and the carrier in a solvent or mixture of solvents, and
(b) removing the solvent or mixture of solvents.
9. Method according to claim 8, wherein the solvent is methanol or the mixture of solvents comprises methanol in an amount of at least 50% v/v.
1
10 Method according to claim 8 or 9, wherein step (a) is carried out at an elevated temperature.
11. An adsorbate obtainable by a method according to any one of claims 8 to 10
12. A pharmaceutical formulation containing enasidenib mesylate in the form of an adsorbate as claimed in any one of claims 1 to 7 or 11 and optionally at least one further pharmaceutical excipient.
13. The pharmaceutical formulation as claimed in claim 12, which is present as a capsule or tablet for oral administration.
14. A method of preparing a tablet, comprising the following steps:
(I) mixing the adsorbate as claimed in any one of claims 1 to 7 or 11 and one or more pharmaceutical excipients;
(II) compressing the mixture from step (I) into a tablet.
15. Use of HPMC-AS, silica and/or magnesium aluminosilicate for stabilizing enasidenib mesylate in amorphous form.
2
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