WO2012130837A1 - Solid agomelatine in non-crystalline form - Google Patents

Solid agomelatine in non-crystalline form Download PDF

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Publication number
WO2012130837A1
WO2012130837A1 PCT/EP2012/055400 EP2012055400W WO2012130837A1 WO 2012130837 A1 WO2012130837 A1 WO 2012130837A1 EP 2012055400 W EP2012055400 W EP 2012055400W WO 2012130837 A1 WO2012130837 A1 WO 2012130837A1
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Prior art keywords
agomelatine
crystalline
composition according
solid
composition
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PCT/EP2012/055400
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French (fr)
Inventor
Ralph Stefan
Daniela Stumm
Sabine PROHL
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Ratiopharm Gmbh
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Publication of WO2012130837A1 publication Critical patent/WO2012130837A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K9/145—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 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
    • A61K9/141—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
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present invention relates to solid, non-crystalline agomelatine, a composition comprising said solid, non-crystalline agomelatine, a pharmaceutical formulation comprising said solid, non-crystalline agomelatine or said composition and methods for the preparation of said composition and formulation.
  • the present invention further relates to a pharmaceutical formulation of agomelatine which does not comprise any binders.
  • Melatonin is a neurohormone that is physiologically synthesized principally in the pineal gland and is involved in the regulation of many physiological and pathophysiological processes such as sleep, seasonal disorders, depression and ageing. Melatonin exhibits its physiological actions by activating G-protein-coupled melatonin receptors MT1 and
  • melatonin Due to its involvement in several physiological and pathophysiological processes, melatonin was considered as a possible therapeutically usable substance. However, its therapeutical usage is limited by the fast metabolic degradation. The plasma half-life of melatonin is only about 15 minutes, which strongly restricts its therapeutical usability.
  • Agomelatine its preparation and use have first been described in EP-A 0 447 285. It is a pharmacological agent with a dual mechanism of action. Similar to melatonin, agomelatine is an agonist of the melatonergic MT1 and MT2 receptors and, additionally, an antagonist of the 5-HT2c receptors.
  • EP-A 0 447 285 discloses a process for the preparation of agomelatine. In this process, agomelatine is obtained by recrystallization from isopropyl ether. No information on the polymorphic form can be found in EP-A 0 447 285. Later publications (e.g. US 2005/0182276) consider that the agomelatine obtained according to that document is the same polymorphic form obtained by Yous et al. in J. Med. Chem. 1992, 35, 1484-1486.
  • WO2005/077887 describes agomelatine form II and processes for the production thereof.
  • US2006/0270876 describes the production of agomelatine form III by melting and slow cooling
  • US2006/0270875 form IV by melting and rapid cooling
  • US2006/0270877 form V by grinding
  • US2010/0036165 form V by spray drying
  • US2009/0069434 form VI US2009/0069434 form VI.
  • US 6,319,520 discloses a solid controlled-release pharmaceutical composition, wherein the composition consists of a thermoformable mixture of at least one active ingredient and of one or more pH independent polymers.
  • the solid pharmaceutical composition can be obtained by the technique of extrusion. There is, however, neither a disclosure of any specific processing parameters nor of the polymorphic form of the active ingredient.
  • Different modifications or solvates of active pharmaceutical substances often exhibit different physical or physicochemical characteristics, such as different melting points, different solubilities, intrinsic dissolution rates, crystal habits, flowabilities, chemical and physical stability, etc. These differences can significantly influence the processability of the active pharmaceutical ingredient or the pharmaceutical formulation. Furthermore, differences in solubility or dissolution rate can significantly influence the pharmacokinetic characteristics of the active pharmaceutical ingredient.
  • agomelatine tends to convert into a different polymorphic form during pharmaceutical processes, e.g. grinding, melting and cooling, or spray drying.
  • US2010/0036165 states that agomelatine form V prepared by grinding has disadvantageous properties regarding its stability.
  • One aspect of the present invention therefore was to provide agomelatine with excellent physical and chemical stability over time.
  • the active ingredient should show good solubility, a fast dissolution rate, good flowability and processability, high stability under usual storage conditions and it should be in a form easily and cost efficiently to be processed into pharmaceutical formulations.
  • a further object of this invention was to provide stable agomelatine compositions that do not lead to retardation of the release of agomelatine from a pharmaceutical formulation containing these compositions.
  • a further object of the present invention was to provide stable pharmaceutical formulations of agomelatine, without binders.
  • the first embodiment of the present invention concerns solid, non-crystalline agomelatine.
  • Another embodiment of the present invention provides the solid, non-crystalline agomelatine of the present invention in a stable form which can be easily processed into pharmaceutical formulations, it is preferable that the non-crystalline agomelatine is in the form of a composition comprising the solid, non-crystalline agomelatine or a pharmaceutically acceptable salt thereof and at least one surface stabilizer.
  • composition of the present invention is in the form of a solid solution of agomelatine or a pharmaceutically acceptable salt thereof wherein the active ingredient is dissolved in the surface stabilizer which acts as solid solvent.
  • Figure 1 shows the DSC of the extrudate according to example 1 described below.
  • Figure 2 shows the DSC of the extrudate according to example 3 described below.
  • Figure 3 shows the DSC of the extrudate according to example 5 described below.
  • Figure 4 shows the XRPD of the extrudate according to example 6 described below.
  • Figure 5 shows the XRPD of a pharmaceutical formulation according to example 2 after four weeks storage at 40 °C and 75 % humidity described below.
  • Figure 6 shows the dissolution profile of the pharmaceutical formulation according to example 2 described below.
  • the DSCs were measured in the range of -50 °C to 140 °C at 10 °C/min. Detailed Description of the Invention
  • a non-crystalline substance can be for example amorphous or in the form of a solid solution.
  • solid non-crystalline substances are isotropic. They usually have no defined melting point, but are gradually converted to the liquid state by a process of slow softening. Experimentally, they can be distinguished from crystalline solids by X-ray diffraction because they do not give sharp interferences; instead they normally show only very few diffuse interferences at small diffraction angles.
  • non-crystalline agomelatine relates to agomelatine which does not contain more than 10 % by weight of crystalline agomelatine, based on the total weight of agomelatine present.
  • the non- crystalline agomelatine contains 0.01 to 10 % of crystalline agomelatine, more preferably 0.1 to 5 % of crystalline agomelatine, each based on the total weight of agomelatine present.
  • the non-crystalline agomelatine contains crystalline agomelatine in an amount such that no defined melting point of crystalline agomelatine can be observed in the DSC.
  • the non-crystalline agomelatine of the present invention is free of crystalline agomelatine.
  • the ratio of crystalline to noncrystalline agomelatine in a given probe can for example be determined by X-ray powder diffraction techniques or by DSC.
  • the non-crystalline agomelatine of the present invention in a stable form which can be easily processed into pharmaceutical formulations it is preferable that the non-crystalline agomelatine is in the form of a composition comprising the solid, non-crystalline agomelatine or a pharmaceutically acceptable salt thereof and at least one surface stabilizer.
  • the surface stabilizer in the composition of the present invention is a substance which is suitable to stabilize agomelatine in its non-crystalline form.
  • the surface stabilizer is mixed with non-crystalline particles of agomelatine.
  • the surface stabilizer is in contact with the non-crystalline agomelatine particles thereby stabilizing its non-crystalline polymorphic form.
  • the non-crystalline agomelatine particles are amorphous.
  • composition of the present invention is in the form of a solid solution of agomelatine or a pharmaceutically acceptable salt thereof wherein the active ingredient is dissolved in the surface stabilizer which acts as solid solvent.
  • solid solution means that agomelatine is present in a molecularly dispersed distribution in a matrix which, at 25°C is present in the solid state.
  • the composition of the present invention should be essentially free of crystalline or amorphous agomelatine particles.
  • the composition in the form of a solid solution should contain less than 15 % by weight, more preferably less than 5 % by weight of amorphous or crystalline agomelatine particles, each referred to the total weight of the agomelatine contained in the solid solution.
  • moly disperse it should preferably be understood that the composition according to the present invention contains no agomeiatine particles with a particle size greater than 300 nm, more preferably greater than 200 nm, particularly greater than 100 nm.
  • the determination of the particle size of any agomeiatine particles, if present, is carried out by means of confocal Raman spectroscopy. As measuring system preferably a NTEGRA spectra nanofinder by NT-MDT is used.
  • the composition of the present invention contains a surface stabilizer.
  • the surface stabilizer is a substance which is suitable to stabilise agomeiatine in amorphous form or in the form of a solid solution.
  • the surface stabilizer is a polymer.
  • the surface stabilizer also comprises substances with polymer-like behaviour. Fats and waxes are examples thereof.
  • the surface stabilizer comprises solid, non-polymeric compounds which preferably possess polar side groups. Sugar alcohols or disaccharides are examples thereof.
  • the surface stabilizer used for the preparation of the composition according to the present invention preferably is a polymer.
  • the polymer usable for the preparation of the composition preferably has a glass-transition temperature (Tg) of greater than 20 °C and of less than 250 °C, more preferably of 30 °C to 200 °C, particularly of 40 °C to 180 °C.
  • Tg glass-transition temperature
  • a polymer with a correspondingly chosen Tg prevents by immobilization the recrystallization of the amorphous agomeiatine or prevents the reconstitution of the molecular agomeiatine dispersion into colloids or particles.
  • glass-transition temperature The temperature at which amorphous or semicrystalline polymers change from the solid state to the liquid state, is designated as "glass-transition temperature" (Tg).
  • Tg glass-transition temperature
  • a clear change of physical characteristic values e.g. the hardness and the elasticity, occurs.
  • a polymer is usually glass-like and hard, above the Tg, it changes to a rubber-like to viscous state.
  • DSC differential scanning calorimetry
  • a Mettler Toledo DSC 1 instrument can be used.
  • Hydrophilic polymers are preferably used for the preparation of the composition. This means polymers possessing hydrophilic groups. Examples for suitable hydrophilic groups are hydroxy, alkoxy, acrylate, sulfonate, carboxylate and quaternary ammonium groups.
  • composition according to the present invention can, for example, comprise the following hydrophilic polymers as surface stabilizer: Polysaccharides, such as hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC, particularly sodium and calcium salts), methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose (HPC), e.g.
  • L-HPC low-substituted hydroxypropylcellulose
  • microcrystalline cellulose polyvinylpyrrolidone, polyvinylacetate (PVAC), polyvinylalcohol (PVA), po!yacrylamide, polymethacrylate, vinylpyrrolidone-vinylacetate-copolymers (for example Kollidon ® VA64, BASF), polyalkylene glycols, such as polypropylene glycol or preferably polyethylene glycol, co-block polymers of polyalkylene glycols, particularly co- block polymers of polyethylene glycol and polypropylene glycol (Pluronic ® , BASF), polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer (Soluplus®, BASF), as well as mixtures of the mentioned polymers.
  • PVAC polyvinylpyrrolidone
  • PVAC polyvinylacetate
  • PVA polyvinylalcohol
  • Polyvinylpyrrolidone preferably with a weight-average molecular weight from 10,000 to 60,000 g/mol, particularly 12,000 to 40,000 g/mol, a copolymer of vinylpyrrolidone and vinylacetate, particularly with a weight-average molecular weight from 40,000 to 70,000 g/mol and/or polyethylene glycol, particularly with a weight-average molecular weight from 2,000 to 10,000 g/mol as well as caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, particularly with a weight-average molecular weight from 100,000 to 120,000 g/mol as well as hydroxypropyl cellulose HPC and HPMC, particularly with a weight-average molecular weight from 20,000 to 90,000 g/mol and/or preferably a proportion of methyl groups of 10 to 35 % and a proportion of hydroxyl groups of 1 to 35 % are preferably used as a surface stabilizer.
  • the composition according to the present invention contains solid, non-crystalline agomelatine (i.e. amorphous agomelatine or agomelatine in the form of a solid solution) and a surface stabilizer, the weight ratio of solid, non-crystalline agomelatine to surface stabilizer being 10 : 1 to 1 : 10, more preferably 5 : 1 to 1 : 5, even more preferably 3 : 1 to 1 : 3, particularly 1 : 1 to 1 : 2.
  • the composition according to the present invention basically consists of non-crystalline agomelatine and one or more surface stabilizers.
  • the composition may additionally contain a crystallization inhibitor, a disintegrant and/or a wicking agent as described below.
  • the composition can basically consist of the non-crystalline agomelatine, the surface stabilizer and one or more of the crystallization inhibitor, disintegrant and wicking agent.
  • “basically” means that small quantities of solvent may still be present in the composition.
  • type and quantity of the surface stabilizer are chosen such that the resulting composition is stable on storage.
  • “Stable on storage” means that in the composition according to the present invention, the proportion of crystalline agomelatine - related to the total quantity of agomelatine - is not more than 60 % by weight, preferably not more than 30 % by weight, more preferably not more than 15 % by weight, particularly not more than 5 % by weight after 3 years of storage at 25 °C and 60 % relative humidity.
  • composition of the present invention may contain further components, in particular pharmaceutically acceptable excipients.
  • the composition may, for example, comprise a crystallization inhibitor, such as an anorganic salt, an organic acid, a sugar alcohol or a high molecular weight polymer.
  • Preferred crystallization inhibitors can be selected from the group of ammonium chloride, citric acid, sorbitol or povidon® K90, particularly preferred citric acid.
  • Other suitable additional components are disintegrants, such as croscarmellose sodium, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone (Crospovidone) and sodium bicarbonate.
  • the composition may contain a wicking agent, in order to increase the dissolution rate of the composition.
  • a wicking agent is able to draw a biological fluid, preferably water, into the composition according to the present invention.
  • Suitable wicking agents can be selected from the group of microcrystalline cellulose, silificized microcrystalline cellulose, colloidal silicium dioxide, kaolin, titanium dioxide, pyrogenous silicic acid, niacine amide, m-pyrole, bentonite, magnesium-aluminium-silicate, polyester, polyethylene, or mixtures thereof.
  • Preferred wicking agents of the present invention are cellulose and cellulose derivatives, such as silificized microcrystalline cellulose, colloidal silicium dioxide, and mixtures thereof.
  • Particularly preferred as wicking agent is silificized microcrystalline cellulose (Prosolv®) with a silicium dioxide content of 1 to 3 % by weight, preferably of 2 % by weight.
  • compositions according to the present invention can be obtained for example by means of melt extrusion, spray drying, or pellet layering.
  • the agomelatine at the beginning of the process is at least partially, preferably fully crystalline and is converted into non-crystalline agomelatine by the step of melt extrusion, spray drying, or pellet layering.
  • non-crystalline agomelatine can be used as starting material.
  • crystalline agomelatine is used as starting material it is important to select the processing parameters such, that the crystalline agomelatine is converted into non-crystalline agomelatine during the process.
  • processing parameters such as heat and in particular shear must be sufficient in order to insure the desired conversion of a crystalline into the desired non-crystalline polymorphic form.
  • Suitable processing parameters can be selected by a person skilled in the art by measuring the amount of remaining crystalline agomelatine in the composition obtained in the process. If the obtained composition still contains a significant amount of crystalline agomelatine for example heat and/or shear in the melt extrusion process can be increased.
  • the invention concerns a melt extrusion process, i.e. a process for the preparation of the composition according to the present invention, comprising the steps of:
  • step (b1) Extrusion of the mixture, the extrusion conditions being chosen such that a transition from crystalline to non-crystalline agomelatine occurs, if the agomelatine in step (a1 ) is at least partially crystalline.
  • Usual melt extruders can be used as extruder, for example a Eurolab Twin Screw Extruder by Thermo Fisher.
  • the extrusion temperature depends on the type of the surface stabilizer. Usually, it is between 80 °C and 250 °C, preferably between 100 °C and 180 °C.
  • the extrusion is preferably carried out at an outlet pressure of 10 bar to 100 bar, more preferably at 20 bar to 80 bar.
  • the invention concerns a spray-drying process for the preparation of the composition according to the present invention, comprising the steps of: (a2) Dissolving of agomelatine and the surface stabilizer in a solvent or solvent mixture, and
  • step (a2) agomelatine and the surface stabilizer described above are dissolved in a solvent or solvent mixture.
  • Crystalline agomelatine can be used as starting material. In such case, however, the spray drying conditions have to be selected such that the crystalline agomelatine is converted into non-crystalline agomelatine.
  • alcohol e.g. methanol, ethanol, isopropanol, butanol, pentanol
  • DMSO dimethyl sulfoxide
  • acetone ethyl acetate, heptane, mixtures thereof or mixtures with water
  • An ethanol/water mixture is used preferably.
  • step (b2) spray drying of the solution from step (a2) is carried out.
  • the spray drying is usually carried out in a spray tower.
  • a Buchi B-191 for example, is suitable (BCichi Labortechnik GmbH, Germany).
  • An inlet temperature of 100 °C to 150 °C is preferably chosen.
  • the air volume is for example 500 to 700 litres/hour and the aspirator runs preferably at 80 to 100 %.
  • the invention concerns a "pellet layering process", i.e. a process for the preparation of a composition according to the present invention, comprising the steps of:
  • step (b3) Spraying of the solution from step (a1) onto a carrier core.
  • step (a3) agomelatine and the surface stabilizer described above are dissolved in a solvent or solvent mixture.
  • Crystalline agomelatine can be used as starting material. In such case, however, the spray drying conditions have to selected such that the crystalline agomelatine is converted into non-crystalline agomelatine.
  • step (b3) spraying of the solution from step (a3) onto a carrier core is conducted.
  • Particles consisting of pharmaceutically compatible excipients, particularly so-called “neutral pellets”, are suitable as carrier cores.
  • Preferably pellets are used which are available under the trade name Cellets ® and contain a mixture of lactose and microcrystalline cellulose or sugar spheres representing a mixture of starch and sugar.
  • Step (b3) is carried out preferably in a fluid bed dryer, for example in a Glatt ® GPCG 3 (Glatt GmbH, Germany). It is usually worked with inlet air temperatures of 50 °C to 100 °C, preferably of 60 °C to 80 °C, with product temperatures of 25 °C to 50 °C, preferably of 30 °C to 40 °C and with a spraying pressure of 0.9 bar to 2.5 bar, preferably of 1 bar to 1.5 bar.
  • a fluid bed dryer for example in a Glatt ® GPCG 3 (Glatt GmbH, Germany. It is usually worked with inlet air temperatures of 50 °C to 100 °C, preferably of 60 °C to 80 °C, with product temperatures of 25 °C to 50 °C, preferably of 30 °C to 40 °C and with a spraying pressure of 0.9 bar to 2.5 bar, preferably of 1 bar to 1.5 bar.
  • composition according to the present invention i.e. the stabilised, non-crystalline agomelatin according to the present invention
  • the composition according to the present invention is usually used for the preparation of a pharmaceutical formulation.
  • the further subject of the invention is, thus, a pharmaceutical formulation, containing a composition according to the present invention.
  • the pharmaceutical formulation may additionally comprise pharmaceutical excipients.
  • excipients known to the expert are concerned, for example such excipients which are described in the European Pharmacopoeia.
  • excipients used are disintegrants, mould release agents, emulsifiers, pseudo-emulsifiers, fillers, additives to improve the powder flowability, glidants, wetting agents, gel-forming agents and/or lubricants. If necessary, further excipients can still be used.
  • the pharmaceutical formulation of the present invention may be in the form of a tablet, capsule, pellets or a granulate.
  • the pharmaceutical formulation of the present invention is an immediate release formulation, in particular an immediate release tablet.
  • the release profile of the formulation is measured in 900 ml of 0.1 N HCI at pH 1 .2 and 37 °C and 75 rpm using the paddle method according to USP using an USP apparatus II.
  • the pharmaceutical formulation of the present invention releases after ten minutes under the above conditions for measuring the release profile not less than 20 %, preferably not less than 30 %, in particular not less than 50 % of its agomelatine content.
  • the pharmaceutical formulation of the present invention releases after thirty minutes under the above conditions for measuring the release profile not less than 60 %, preferably not less than 70 %, in particular not less than 80 % of its agomelatine content.
  • the present invention relates to a pharmaceutical formulation comprising agomelatine or a pharmaceutical acceptable salt thereof which is substantially free of any binder.
  • the formulation preferably comprises solid, noncrystalline agomelatine or a composition comprising non-crystalline agomelatine as described above.
  • Example 1 Preparation of a composition comprising agomelatine in non-crystalline form by melt extrusion together with polyvinylpyrrolidone
  • Example 2 Pharmaceutical composition comprising the agomelatine composition prepared according to example 1
  • Example 3 Preparation of a composition comprising agomelatine in non-crystalline form by melt extrusion together with polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer
  • Example 4 Pharmaceutical composition comprising the agomelatine composition prepared according to example 3
  • the resulting powder from example 3 was mixed with 40.56 g microcrystalline cellulose, 10.4 g of crosslinked polyvinylpyrrolidone (Kollidon® CL), 0.52 g of silicon dioxide (Aerosil®), 0.52 g of magnesium stearate and the resulting mixture was compressed to a tablet on an excenter press (Korsch EK0).
  • Example 5 Preparation of a composition comprising agomelatine in non-crystalline form by melt extrusion together with hydroxypropyl cellulose
  • Example 6 Preparation of a composition comprising agomelatine in non-crystalline form by melt extrusion together with polyvinylpyrrolidone and a crystllization inhibitor
  • Example 7 Pharmaceutical composition comprising the Agomeiatine composition prepared according to example 6
  • the resulting powder from example 6 was mixed with 21 .08 g of microcrystalline cellulose (Avicel® 102), 10.4 g of crosslinked polyvinylpyrrolidone (Kollidon® CL), 0.52 g of silicon dioxide (Aerosil®), 0.52 g of magnesium Stearate, and the resulting mixture was compressed to a tablet on an excenter press (Korsch EK0).
  • Example 8a Formulation of agomeiatine without binder by wet granulation
  • Agomeiatine was mixed together with maize starch and a first part of lactose monohydrate and granulated with water. The resulting granulate was dried to starting moisture level. The remaining lactose monohydrate, croscarmellose sodium, stearic acid and silica were added to the granulate, mixed for 5 min in a Turbula mixer and sieved. Sieved magnesium stearate was added, the mixture was mixed for additional 1 ,5 min. The resulting powder composition was compressed on a Korsch EK0 excenter press.
  • Example 8b Formulation of agomeiatine without binder by wet granulation
  • Agomeiatine was mixed together with isomalt and granulated with water. The resulting granulate was dried to starting moisture level. Croscarmellose sodium was added to the granulate, mixed for 1.5 min in a Turbula mixer and sieved. Sieved magnesium stearate was added, the mixture was mixed for additional 1 .5 min. The resulting powder composition was compressed on a Korsch EKO excenter press.
  • Example 9a Formulation of agomeiatine without binder by direct compression
  • Agomeiatine was mixed together with isomalt and croscarmellose sodium, mixed for 5 min in a Turbula mixer and sieved. Sieved magnesium stearate was added, the mixture was mixed for additional 1.5 min. The resulting powder composition was compressed on a Korsch EKO excenter press.
  • Example 9b Formulation of agomeiatine without binder by direct compression
  • Agomeiatine was mixed together with calcium hydrogen phosphate and croscarmellose sodium, mixed for 5 min in a Turbula mixer and sieved. Sieved magnesium stearate was added, the mixture was mixed for additional 1 .5 min. The resulting powder composition was compressed on a Korsch EKO excenter press.
  • Example 10 Stability test of pharmaceutical formulation according to example 2
  • Tablets prepared according to example 2 were stored in closed bottles at a temperature of 40 °C and a relative humidity of 75 % for four weeks. After the storage time tablets were milled in a mortar and analysed by DSC. The resulting powder did not show any significant reflexes in XRPD confirming non-crystallinity (figure 5).

Abstract

The present invention relates to solid, non-crystalline agomelatine, a composition comprising said solid, non-crystalline agomelatine, a pharmaceutical formulation comprising said solid, non-crystalline agomelatine or said composition and methods for the preparation of said composition and formulation.

Description

Solid Agomelatine in Non-Crystalline Form
The present invention relates to solid, non-crystalline agomelatine, a composition comprising said solid, non-crystalline agomelatine, a pharmaceutical formulation comprising said solid, non-crystalline agomelatine or said composition and methods for the preparation of said composition and formulation.
The present invention further relates to a pharmaceutical formulation of agomelatine which does not comprise any binders.
Melatonin is a neurohormone that is physiologically synthesized principally in the pineal gland and is involved in the regulation of many physiological and pathophysiological processes such as sleep, seasonal disorders, depression and ageing. Melatonin exhibits its physiological actions by activating G-protein-coupled melatonin receptors MT1 and
MT2.
Due to its involvement in several physiological and pathophysiological processes, melatonin was considered as a possible therapeutically usable substance. However, its therapeutical usage is limited by the fast metabolic degradation. The plasma half-life of melatonin is only about 15 minutes, which strongly restricts its therapeutical usability.
Research efforts have been made for structurally modified melatonin analogues which maintain the pharmacological activity of melatonin but which have improved pharmacokinetic properties. As a result of this research the bioisosterically modified melatonin analogue agomelatine attracted attention as a suitable therapeutic substance. Agomelatine has the chemical name A/-[2-(7-methoxy-1 -naphthyl)ethyl]acetamide and has the following chemical structure:
Figure imgf000002_0001
Agomelatine, its preparation and use have first been described in EP-A 0 447 285. It is a pharmacological agent with a dual mechanism of action. Similar to melatonin, agomelatine is an agonist of the melatonergic MT1 and MT2 receptors and, additionally, an antagonist of the 5-HT2c receptors.
When developing agomelatine formulations, the inventors of the present application were confronted with the fact that crystalline agomelatine can exist in different crystalline, polymorphic forms. EP-A 0 447 285 discloses a process for the preparation of agomelatine. In this process, agomelatine is obtained by recrystallization from isopropyl ether. No information on the polymorphic form can be found in EP-A 0 447 285. Later publications (e.g. US 2005/0182276) consider that the agomelatine obtained according to that document is the same polymorphic form obtained by Yous et al. in J. Med. Chem. 1992, 35, 1484-1486.
WO2005/077887 describes agomelatine form II and processes for the production thereof. US2006/0270876 describes the production of agomelatine form III by melting and slow cooling, US2006/0270875 form IV by melting and rapid cooling, US2006/0270877 form V by grinding, US2010/0036165 form V by spray drying, and US2009/0069434 form VI.
US 6,319,520 discloses a solid controlled-release pharmaceutical composition, wherein the composition consists of a thermoformable mixture of at least one active ingredient and of one or more pH independent polymers. The solid pharmaceutical composition can be obtained by the technique of extrusion. There is, however, neither a disclosure of any specific processing parameters nor of the polymorphic form of the active ingredient.
Different modifications or solvates of active pharmaceutical substances often exhibit different physical or physicochemical characteristics, such as different melting points, different solubilities, intrinsic dissolution rates, crystal habits, flowabilities, chemical and physical stability, etc. These differences can significantly influence the processability of the active pharmaceutical ingredient or the pharmaceutical formulation. Furthermore, differences in solubility or dissolution rate can significantly influence the pharmacokinetic characteristics of the active pharmaceutical ingredient.
From the cited patent literature it is also known that agomelatine tends to convert into a different polymorphic form during pharmaceutical processes, e.g. grinding, melting and cooling, or spray drying. US2010/0036165 states that agomelatine form V prepared by grinding has disadvantageous properties regarding its stability.
Summary of the Invention
One aspect of the present invention therefore was to provide agomelatine with excellent physical and chemical stability over time. The active ingredient should show good solubility, a fast dissolution rate, good flowability and processability, high stability under usual storage conditions and it should be in a form easily and cost efficiently to be processed into pharmaceutical formulations.
A further object of this invention was to provide stable agomelatine compositions that do not lead to retardation of the release of agomelatine from a pharmaceutical formulation containing these compositions.
A further object of the present invention was to provide stable pharmaceutical formulations of agomelatine, without binders.
The first embodiment of the present invention concerns solid, non-crystalline agomelatine.
Another embodiment of the present invention provides the solid, non-crystalline agomelatine of the present invention in a stable form which can be easily processed into pharmaceutical formulations, it is preferable that the non-crystalline agomelatine is in the form of a composition comprising the solid, non-crystalline agomelatine or a pharmaceutically acceptable salt thereof and at least one surface stabilizer.
In a further embodiment the composition of the present invention is in the form of a solid solution of agomelatine or a pharmaceutically acceptable salt thereof wherein the active ingredient is dissolved in the surface stabilizer which acts as solid solvent.
Brief Description of the Drawings
Figure 1 shows the DSC of the extrudate according to example 1 described below. Figure 2 shows the DSC of the extrudate according to example 3 described below. Figure 3 shows the DSC of the extrudate according to example 5 described below.
Figure 4 shows the XRPD of the extrudate according to example 6 described below.
Figure 5 shows the XRPD of a pharmaceutical formulation according to example 2 after four weeks storage at 40 °C and 75 % humidity described below.
Figure 6 shows the dissolution profile of the pharmaceutical formulation according to example 2 described below.
The DSCs were measured in the range of -50 °C to 140 °C at 10 °C/min. Detailed Description of the Invention
The term "non-crystalline" is used in the framework of this invention as designation for the state of solid substances, at which the components (atoms, ions or molecules, i.e. in the case of agomelatine the agomelatine molecules) exhibit no periodic arrangement over a larger area (= long-range order). In non-crystalline substances, the components are usually not arranged completely randomly and purely statistically, but they are distributed such that a certain regularity and similarity with the crystalline state are discernible only with respect to distance and orientation of the nearest neighbours (= short-range order). Consequently, non-crystalline substances preferably have a short-range order but no long- range order. A non-crystalline substance can be for example amorphous or in the form of a solid solution.
In contrast to the anisotropic crystals, solid non-crystalline substances are isotropic. They usually have no defined melting point, but are gradually converted to the liquid state by a process of slow softening. Experimentally, they can be distinguished from crystalline solids by X-ray diffraction because they do not give sharp interferences; instead they normally show only very few diffuse interferences at small diffraction angles.
Within the scope of the present invention, the expression "non-crystalline agomelatine" relates to agomelatine which does not contain more than 10 % by weight of crystalline agomelatine, based on the total weight of agomelatine present. Preferably, the non- crystalline agomelatine contains 0.01 to 10 % of crystalline agomelatine, more preferably 0.1 to 5 % of crystalline agomelatine, each based on the total weight of agomelatine present. In a further preferred embodiment the non-crystalline agomelatine contains crystalline agomelatine in an amount such that no defined melting point of crystalline agomelatine can be observed in the DSC. Most preferred the non-crystalline agomelatine of the present invention is free of crystalline agomelatine. The ratio of crystalline to noncrystalline agomelatine in a given probe can for example be determined by X-ray powder diffraction techniques or by DSC.
In order to provide the solid, non-crystalline agomelatine of the present invention in a stable form which can be easily processed into pharmaceutical formulations it is preferable that the non-crystalline agomelatine is in the form of a composition comprising the solid, non-crystalline agomelatine or a pharmaceutically acceptable salt thereof and at least one surface stabilizer.
The surface stabilizer in the composition of the present invention is a substance which is suitable to stabilize agomelatine in its non-crystalline form.
In one embodiment of the composition of the present invention the surface stabilizer is mixed with non-crystalline particles of agomelatine. In this embodiment the surface stabilizer is in contact with the non-crystalline agomelatine particles thereby stabilizing its non-crystalline polymorphic form. In this embodiment the non-crystalline agomelatine particles are amorphous.
In a further embodiment the composition of the present invention is in the form of a solid solution of agomelatine or a pharmaceutically acceptable salt thereof wherein the active ingredient is dissolved in the surface stabilizer which acts as solid solvent. The term "solid solution" means that agomelatine is present in a molecularly dispersed distribution in a matrix which, at 25°C is present in the solid state.
If the composition of the present invention is present as solid solution, the composition should be essentially free of crystalline or amorphous agomelatine particles. Preferably, the composition in the form of a solid solution should contain less than 15 % by weight, more preferably less than 5 % by weight of amorphous or crystalline agomelatine particles, each referred to the total weight of the agomelatine contained in the solid solution. Furthermore, by "molecularly disperse" it should preferably be understood that the composition according to the present invention contains no agomeiatine particles with a particle size greater than 300 nm, more preferably greater than 200 nm, particularly greater than 100 nm. The determination of the particle size of any agomeiatine particles, if present, is carried out by means of confocal Raman spectroscopy. As measuring system preferably a NTEGRA spectra nanofinder by NT-MDT is used.
In the above two embodiments the composition of the present invention contains a surface stabilizer. Generally, the surface stabilizer is a substance which is suitable to stabilise agomeiatine in amorphous form or in the form of a solid solution. Preferably, the surface stabilizer is a polymer. Furthermore, the surface stabilizer also comprises substances with polymer-like behaviour. Fats and waxes are examples thereof. In addition, the surface stabilizer comprises solid, non-polymeric compounds which preferably possess polar side groups. Sugar alcohols or disaccharides are examples thereof.
The surface stabilizer used for the preparation of the composition according to the present invention preferably is a polymer. The polymer usable for the preparation of the composition preferably has a glass-transition temperature (Tg) of greater than 20 °C and of less than 250 °C, more preferably of 30 °C to 200 °C, particularly of 40 °C to 180 °C. A polymer with a correspondingly chosen Tg prevents by immobilization the recrystallization of the amorphous agomeiatine or prevents the reconstitution of the molecular agomeiatine dispersion into colloids or particles.
The temperature at which amorphous or semicrystalline polymers change from the solid state to the liquid state, is designated as "glass-transition temperature" (Tg). In this process, a clear change of physical characteristic values, e.g. the hardness and the elasticity, occurs. Below the Tg, a polymer is usually glass-like and hard, above the Tg, it changes to a rubber-like to viscous state. The determination of the glass-transition temperature is carried out by means of differential scanning calorimetry (DSC). For this, a Mettler Toledo DSC 1 instrument can be used. It is worked with a heating rate of 1 -20 °C/min, preferably 5-15 °C/min or with a cooling rate of 20-60 °C/min, preferably 30-55 °C/min. Hydrophilic polymers are preferably used for the preparation of the composition. This means polymers possessing hydrophilic groups. Examples for suitable hydrophilic groups are hydroxy, alkoxy, acrylate, sulfonate, carboxylate and quaternary ammonium groups.
The composition according to the present invention can, for example, comprise the following hydrophilic polymers as surface stabilizer: Polysaccharides, such as hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC, particularly sodium and calcium salts), methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose (HPC), e.g. L-HPC (low-substituted hydroxypropylcellulose); microcrystalline cellulose, polyvinylpyrrolidone, polyvinylacetate (PVAC), polyvinylalcohol (PVA), po!yacrylamide, polymethacrylate, vinylpyrrolidone-vinylacetate-copolymers (for example Kollidon® VA64, BASF), polyalkylene glycols, such as polypropylene glycol or preferably polyethylene glycol, co-block polymers of polyalkylene glycols, particularly co- block polymers of polyethylene glycol and polypropylene glycol (Pluronic®, BASF), polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer (Soluplus®, BASF), as well as mixtures of the mentioned polymers.
Polyvinylpyrrolidone, preferably with a weight-average molecular weight from 10,000 to 60,000 g/mol, particularly 12,000 to 40,000 g/mol, a copolymer of vinylpyrrolidone and vinylacetate, particularly with a weight-average molecular weight from 40,000 to 70,000 g/mol and/or polyethylene glycol, particularly with a weight-average molecular weight from 2,000 to 10,000 g/mol as well as caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, particularly with a weight-average molecular weight from 100,000 to 120,000 g/mol as well as hydroxypropyl cellulose HPC and HPMC, particularly with a weight-average molecular weight from 20,000 to 90,000 g/mol and/or preferably a proportion of methyl groups of 10 to 35 % and a proportion of hydroxyl groups of 1 to 35 % are preferably used as a surface stabilizer.
In a preferred embodiment, the composition according to the present invention contains solid, non-crystalline agomelatine (i.e. amorphous agomelatine or agomelatine in the form of a solid solution) and a surface stabilizer, the weight ratio of solid, non-crystalline agomelatine to surface stabilizer being 10 : 1 to 1 : 10, more preferably 5 : 1 to 1 : 5, even more preferably 3 : 1 to 1 : 3, particularly 1 : 1 to 1 : 2. Particularly, the composition according to the present invention basically consists of non-crystalline agomelatine and one or more surface stabilizers. Alternatively the composition may additionally contain a crystallization inhibitor, a disintegrant and/or a wicking agent as described below. In such case the composition can basically consist of the non-crystalline agomelatine, the surface stabilizer and one or more of the crystallization inhibitor, disintegrant and wicking agent. In this regard "basically" means that small quantities of solvent may still be present in the composition.
It is preferred that type and quantity of the surface stabilizer are chosen such that the resulting composition is stable on storage. "Stable on storage" means that in the composition according to the present invention, the proportion of crystalline agomelatine - related to the total quantity of agomelatine - is not more than 60 % by weight, preferably not more than 30 % by weight, more preferably not more than 15 % by weight, particularly not more than 5 % by weight after 3 years of storage at 25 °C and 60 % relative humidity.
In addition to the surface stabilizer the composition of the present invention may contain further components, in particular pharmaceutically acceptable excipients. If required the composition may, for example, comprise a crystallization inhibitor, such as an anorganic salt, an organic acid, a sugar alcohol or a high molecular weight polymer. Preferred crystallization inhibitors can be selected from the group of ammonium chloride, citric acid, sorbitol or povidon® K90, particularly preferred citric acid. Other suitable additional components are disintegrants, such as croscarmellose sodium, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone (Crospovidone) and sodium bicarbonate. Alternatively or in addition to the disintegrant the composition may contain a wicking agent, in order to increase the dissolution rate of the composition. Generally, a wicking agent is able to draw a biological fluid, preferably water, into the composition according to the present invention. Suitable wicking agents can be selected from the group of microcrystalline cellulose, silificized microcrystalline cellulose, colloidal silicium dioxide, kaolin, titanium dioxide, pyrogenous silicic acid, niacine amide, m-pyrole, bentonite, magnesium-aluminium-silicate, polyester, polyethylene, or mixtures thereof. Preferred wicking agents of the present invention are cellulose and cellulose derivatives, such as silificized microcrystalline cellulose, colloidal silicium dioxide, and mixtures thereof. Particularly preferred as wicking agent is silificized microcrystalline cellulose (Prosolv®) with a silicium dioxide content of 1 to 3 % by weight, preferably of 2 % by weight.
Compositions according to the present invention can be obtained for example by means of melt extrusion, spray drying, or pellet layering. In this process it is preferred that the agomelatine at the beginning of the process is at least partially, preferably fully crystalline and is converted into non-crystalline agomelatine by the step of melt extrusion, spray drying, or pellet layering. Alternatively non-crystalline agomelatine can be used as starting material.
If crystalline agomelatine is used as starting material it is important to select the processing parameters such, that the crystalline agomelatine is converted into non-crystalline agomelatine during the process. For example not all melt extrusion processes are suitable for converting crystalline into non-crystalline agomelatine. Heat and in particular shear must be sufficient in order to insure the desired conversion of a crystalline into the desired non-crystalline polymorphic form. Suitable processing parameters can be selected by a person skilled in the art by measuring the amount of remaining crystalline agomelatine in the composition obtained in the process. If the obtained composition still contains a significant amount of crystalline agomelatine for example heat and/or shear in the melt extrusion process can be increased.
In a first embodiment, the invention concerns a melt extrusion process, i.e. a process for the preparation of the composition according to the present invention, comprising the steps of:
(a1 ) Mixing of agomelatine and a surface stabilizer, and
(b1) Extrusion of the mixture, the extrusion conditions being chosen such that a transition from crystalline to non-crystalline agomelatine occurs, if the agomelatine in step (a1 ) is at least partially crystalline.
Usual melt extruders can be used as extruder, for example a Eurolab Twin Screw Extruder by Thermo Fisher.
The extrusion temperature depends on the type of the surface stabilizer. Usually, it is between 80 °C and 250 °C, preferably between 100 °C and 180 °C. The extrusion is preferably carried out at an outlet pressure of 10 bar to 100 bar, more preferably at 20 bar to 80 bar.
In a second embodiment, the invention concerns a spray-drying process for the preparation of the composition according to the present invention, comprising the steps of: (a2) Dissolving of agomelatine and the surface stabilizer in a solvent or solvent mixture, and
(b2) Spray drying of the solution from step (a2).
In step (a2), agomelatine and the surface stabilizer described above are dissolved in a solvent or solvent mixture. Crystalline agomelatine can be used as starting material. In such case, however, the spray drying conditions have to be selected such that the crystalline agomelatine is converted into non-crystalline agomelatine.
For example alcohol (e.g. methanol, ethanol, isopropanol, butanol, pentanol), dimethyl sulfoxide (DMSO), acetone, ethyl acetate, heptane, mixtures thereof or mixtures with water are suitable as solvents. An ethanol/water mixture is used preferably.
In the subsequent step (b2), spray drying of the solution from step (a2) is carried out. The spray drying is usually carried out in a spray tower. A Buchi B-191 , for example, is suitable (BCichi Labortechnik GmbH, Germany). An inlet temperature of 100 °C to 150 °C is preferably chosen. The air volume is for example 500 to 700 litres/hour and the aspirator runs preferably at 80 to 100 %.
In a third embodiment, the invention concerns a "pellet layering process", i.e. a process for the preparation of a composition according to the present invention, comprising the steps of:
(a3) Dissolving of the agomelatine and of the surface stabilizer in a solvent or solvent mixture, and
(b3) Spraying of the solution from step (a1) onto a carrier core.
In step (a3), agomelatine and the surface stabilizer described above are dissolved in a solvent or solvent mixture. Crystalline agomelatine can be used as starting material. In such case, however, the spray drying conditions have to selected such that the crystalline agomelatine is converted into non-crystalline agomelatine.
As solvents those solvents as described above with respect to spray drying are suitable. In step (b3), spraying of the solution from step (a3) onto a carrier core is conducted. Particles consisting of pharmaceutically compatible excipients, particularly so-called "neutral pellets", are suitable as carrier cores. Preferably pellets are used which are available under the trade name Cellets® and contain a mixture of lactose and microcrystalline cellulose or sugar spheres representing a mixture of starch and sugar.
Step (b3) is carried out preferably in a fluid bed dryer, for example in a Glatt® GPCG 3 (Glatt GmbH, Germany). It is usually worked with inlet air temperatures of 50 °C to 100 °C, preferably of 60 °C to 80 °C, with product temperatures of 25 °C to 50 °C, preferably of 30 °C to 40 °C and with a spraying pressure of 0.9 bar to 2.5 bar, preferably of 1 bar to 1.5 bar.
The composition according to the present invention (i.e. the stabilised, non-crystalline agomelatin according to the present invention) is usually used for the preparation of a pharmaceutical formulation.
The further subject of the invention is, thus, a pharmaceutical formulation, containing a composition according to the present invention. The pharmaceutical formulation may additionally comprise pharmaceutical excipients.
In this connection, excipients known to the expert are concerned, for example such excipients which are described in the European Pharmacopoeia.
Examples for excipients used are disintegrants, mould release agents, emulsifiers, pseudo-emulsifiers, fillers, additives to improve the powder flowability, glidants, wetting agents, gel-forming agents and/or lubricants. If necessary, further excipients can still be used.
The pharmaceutical formulation of the present invention may be in the form of a tablet, capsule, pellets or a granulate. Preferred are tablets, such as film coated tablets.
In a further preferred embodiment the pharmaceutical formulation of the present invention is an immediate release formulation, in particular an immediate release tablet. The release profile of the formulation is measured in 900 ml of 0.1 N HCI at pH 1 .2 and 37 °C and 75 rpm using the paddle method according to USP using an USP apparatus II. In a preferred embodiment the pharmaceutical formulation of the present invention releases after ten minutes under the above conditions for measuring the release profile not less than 20 %, preferably not less than 30 %, in particular not less than 50 % of its agomelatine content. In a preferred embodiment the pharmaceutical formulation of the present invention releases after thirty minutes under the above conditions for measuring the release profile not less than 60 %, preferably not less than 70 %, in particular not less than 80 % of its agomelatine content.
In a further embodiment the present invention relates to a pharmaceutical formulation comprising agomelatine or a pharmaceutical acceptable salt thereof which is substantially free of any binder. In this embodiment the formulation preferably comprises solid, noncrystalline agomelatine or a composition comprising non-crystalline agomelatine as described above.
The invention is now illustrated by way of examples which are not intended to be construed as limiting.
Examples:
Example 1 : Preparation of a composition comprising agomelatine in non-crystalline form by melt extrusion together with polyvinylpyrrolidone
20 g of agomelatine and 32 g of polyvinylpyrrolidone (Kollidon® 25) were mixed and extruded in a ThermoFisher extruder at 200°C. The resulting extrudate was milled and sieved. The resulting powder showed no melting point in DSC, but a glass transition temperature at 27.0°C confirming non-crystallinity (figure 1).
Example 2: Pharmaceutical composition comprising the agomelatine composition prepared according to example 1
The resulting powder from example 1 was mixed with 40.56 g of microcrystalline cellulose, 10,4 g of crosslinked polyvinylpyrrolidone (Kollidon® CL), 0.52 g of silicon dioxide (Aerosil®), 0.52 g of magnesium stearate and the resulting mixture was compressed to a tablet on an excenter press (Korsch EK0). Example 3: Preparation of a composition comprising agomelatine in non-crystalline form by melt extrusion together with polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer
20 g of agomelatine and 32 g of polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer (Soluplus®, BASF) were mixed and extruded in a ThermoFisher extruder at 200 °C. The resulting extrudate was milled and sieved. The resulting powder showed no melting point in DSC, but a glass transition temperature at 49.0 °C confirming noncrystalline (figure 2).
Example 4: Pharmaceutical composition comprising the agomelatine composition prepared according to example 3
The resulting powder from example 3 was mixed with 40.56 g microcrystalline cellulose, 10.4 g of crosslinked polyvinylpyrrolidone (Kollidon® CL), 0.52 g of silicon dioxide (Aerosil®), 0.52 g of magnesium stearate and the resulting mixture was compressed to a tablet on an excenter press (Korsch EK0).
Example 5: Preparation of a composition comprising agomelatine in non-crystalline form by melt extrusion together with hydroxypropyl cellulose
20 g of agomelatine and 24 g of hydroxypropyl cellulose (Klucel® EF) were mixed and extruded in a ThermoFisher extruder at 120 °C. The resulting extrudate was milled and sieved. The resulting powder showed no melting point in DSC, but a glass transition temperature at 3.3 °C confirming non-crystallinity (figure 3).
Example 6: Preparation of a composition comprising agomelatine in non-crystalline form by melt extrusion together with polyvinylpyrrolidone and a crystllization inhibitor
20 g agomelatine, 40 g of polyvinylpyrrolidone (Kollidon® 25) and 20 g of citric acid were mixed and extruded in a ThermoFisher extruder at 200 °C. The resulting extrudate was milled and sieved. The resulting powder did not show any significant reflexes in XRPD confirming non-crystallinity (figure 4). Example 7: Pharmaceutical composition comprising the Agomeiatine composition prepared according to example 6
The resulting powder from example 6 was mixed with 21 .08 g of microcrystalline cellulose (Avicel® 102), 10.4 g of crosslinked polyvinylpyrrolidone (Kollidon® CL), 0.52 g of silicon dioxide (Aerosil®), 0.52 g of magnesium Stearate, and the resulting mixture was compressed to a tablet on an excenter press (Korsch EK0).
Example 8a: Formulation of agomeiatine without binder by wet granulation
Agomeiatine 25.00 mg
Maize starch 25.59 mg
Lactose monohydrate 70.05 mg
Water 5.00 mg
Croscarmellose sodium 5.20 mg
Stearic acid 2.60 mg
Aerosil 0.26 mg
Magnesium stearate 1.30 mg
Agomeiatine was mixed together with maize starch and a first part of lactose monohydrate and granulated with water. The resulting granulate was dried to starting moisture level. The remaining lactose monohydrate, croscarmellose sodium, stearic acid and silica were added to the granulate, mixed for 5 min in a Turbula mixer and sieved. Sieved magnesium stearate was added, the mixture was mixed for additional 1 ,5 min. The resulting powder composition was compressed on a Korsch EK0 excenter press.
Example 8b: Formulation of agomeiatine without binder by wet granulation
Agomeiatine 25.00 mg
Isomalt (GalenlQ® 721) 90.70 mg
Water 5.00 mg
Croscarmellose sodium 13.20 mg
Magnesium stearate 1 .30 mg
Agomeiatine was mixed together with isomalt and granulated with water. The resulting granulate was dried to starting moisture level. Croscarmellose sodium was added to the granulate, mixed for 1.5 min in a Turbula mixer and sieved. Sieved magnesium stearate was added, the mixture was mixed for additional 1 .5 min. The resulting powder composition was compressed on a Korsch EKO excenter press.
Example 9a: Formulation of agomeiatine without binder by direct compression
Agomelatin 25.00 mg
Isomalt (GalenlQ® 721) 90.70 mg
Croscarmellose sodium 13.00 mg
Magnesium stearate 1 .30 mg
Agomeiatine was mixed together with isomalt and croscarmellose sodium, mixed for 5 min in a Turbula mixer and sieved. Sieved magnesium stearate was added, the mixture was mixed for additional 1.5 min. The resulting powder composition was compressed on a Korsch EKO excenter press.
Example 9b: Formulation of agomeiatine without binder by direct compression
Agomeiatine 25.00 mg
Calcium hydrogen phosphate 90.70 mg
Croscarmellose sodium 13.00 mg
Magnesium stearate 1.30 mg
Agomeiatine was mixed together with calcium hydrogen phosphate and croscarmellose sodium, mixed for 5 min in a Turbula mixer and sieved. Sieved magnesium stearate was added, the mixture was mixed for additional 1 .5 min. The resulting powder composition was compressed on a Korsch EKO excenter press.
Example 10: Stability test of pharmaceutical formulation according to example 2
Tablets prepared according to example 2 were stored in closed bottles at a temperature of 40 °C and a relative humidity of 75 % for four weeks. After the storage time tablets were milled in a mortar and analysed by DSC. The resulting powder did not show any significant reflexes in XRPD confirming non-crystallinity (figure 5).

Claims

Claims
1 . Solid, non-crystalline agomelatine or a pharmaceutically acceptable salt thereof.
2. Composition comprising solid, non-crystalline agomelatine according to claim 1 and at least one surface stabilizer.
3. Composition according to claim 2 which comprises amorphous agomelatine particles and the surface stabilizer.
4. Composition according to claim 2 in the form of a solid solution of agomelatine in the surface stabilizer as solid solvent.
5. Composition according to any one of claims 2-4, wherein the surface stabilizer is selected from the group consisting of fats, waxes, polymers and non-polymeric compounds which preferably possess polar side chains, such as sugar alcohols or disaccharides.
6. Composition according to claim 5, wherein the polymers are selected from the group consisting of polysaccharides, microcrystalline cellulose, polyvinylpyrrolidone, polyvinylacetate, polyvinylalcohol, polyacrylamide, polymethacrylate, vinylpyrrolidone-vinylacetate-copolymers, polyalkylene glycols, co-block polymers of polyalkylene glycols, polyvinyl caprolactam-polyvinylacetate- polyethylene glycol graft copolymer, as well as mixtures thereof.
7. Composition according to any one of claims 2-6, wherein the weight ratio of agomelatine to surface stabilizer is in the range of 10: 1 to 1 : 10.
8. Composition according to any one of claims 2-7, further comprising a crystallization inhibitor, disintegrant and/or a wicking agent.
9. Process of preparing a composition according to any one of claims 1 -8, which comprises the step of melt extrusion, spray drying, or pellet layering.
10. Process according to claim 9, wherein the agomelatine at the beginning of the process is at least partially crystalline and is converted into non-crystalline agomelatine by the step of melt extrusion, spray drying, or pellet layering.
1 1 . Use of a composition according to any one of claims 1 -8 for the manufacturer of a pharmaceutical formulation.
12. Pharmaceutical formulation comprising solid, non-crystalline agomelatine or a pharmaceutically acceptable salt thereof according to claim 1 or a composition according to any one of claims 2-8.
13. Pharmaceutical formulation comprising agomelatine or a pharmaceutically acceptable salt thereof which is substantially free of any binder.
14. Pharmaceutical formulation according to claim 13 comprising solid, non-crystalline agomelatine or a pharmaceutically acceptable salt thereof according to claim 1 or a composition according to any one of claims 2-8.
PCT/EP2012/055400 2011-03-28 2012-03-27 Solid agomelatine in non-crystalline form WO2012130837A1 (en)

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WO2014040228A1 (en) * 2012-09-11 2014-03-20 Les Laboratoires Servier Stabilised amorphous form of agomelatine, a process for its preparation and pharmaceutical compositions containing it
JP2015529215A (en) * 2012-09-11 2015-10-05 レ ラボラトワール セルヴィエ Stabilized amorphous form of agomelatin, process for its preparation and pharmaceutical composition containing the same
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WO2014122405A1 (en) * 2013-02-08 2014-08-14 Les Laboratoires Servier Solid pharmaceutical composition for oral delivery of agomelatine
WO2014187229A1 (en) * 2013-05-20 2014-11-27 杭州领业医药科技有限公司 Preparation method for agomelatine crystal form i
CN104379557A (en) * 2013-05-20 2015-02-25 杭州领业医药科技有限公司 Preparation method for agomelatine crystal form I
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WO2015124496A1 (en) 2014-02-19 2015-08-27 Synthon B.V. Pharmaceutical composition comprising amorphous agomelatine
EP3075724A1 (en) 2015-03-31 2016-10-05 F.I.S.- Fabbrica Italiana Sintetici S.p.A. Solid form of agomelatine
RU2587331C1 (en) * 2015-06-19 2016-06-20 Общество с ограниченной ответственностью "Полигепазол" Method of producing pharmaceutical composition ademetionine and dosage form thereof
EP3466413A1 (en) 2017-10-09 2019-04-10 KRKA, d.d., Novo mesto Pharmaceutical composition containing agomelatine and process for the preparation thereof
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