WO2015021949A1 - Solution d'agomélatine solide et thermodynamiquement stable destinée à être utilisée dans une préparation pharmaceutique - Google Patents

Solution d'agomélatine solide et thermodynamiquement stable destinée à être utilisée dans une préparation pharmaceutique Download PDF

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Publication number
WO2015021949A1
WO2015021949A1 PCT/CZ2014/000088 CZ2014000088W WO2015021949A1 WO 2015021949 A1 WO2015021949 A1 WO 2015021949A1 CZ 2014000088 W CZ2014000088 W CZ 2014000088W WO 2015021949 A1 WO2015021949 A1 WO 2015021949A1
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WO
WIPO (PCT)
Prior art keywords
agomelatine
accordance
solid solution
weight
pharmaceutical composition
Prior art date
Application number
PCT/CZ2014/000088
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English (en)
Inventor
Jaroslav Rezac
Anna Hanovska
Daniel Pribyl
Ondrej Dammer
AIena PROKOPOVA
Original Assignee
Zentiva, K.S.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by Zentiva, K.S. filed Critical Zentiva, K.S.
Publication of WO2015021949A1 publication Critical patent/WO2015021949A1/fr

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Classifications

    • 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
    • A61K31/16—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
    • A61K9/20—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

Definitions

  • the invention relates to pharmaceutical compositions containing a solid solution of agomelatine (N-[2-(7-methoxy-1-naphtyl)ethyl]acetamide) of formula (I),
  • Formulations containing agomelatine belong to the group of antidepressants.
  • Agomelatine is a melatonergic agonist (of the ⁇ and MT 2 receptors) and an antagonist of the 5-HT 2 c serotonergic receptors.
  • Agomelatine was first introduced in the patent EP 0 447 285 (Adir et Compagnie).
  • agomelatine There are a number of polymorphic forms of agomelatine.
  • the application WO2005077887 (Servier) describes Form II of agomelatine
  • the application WO2007015003 (Servier) describes Form III of agomelatine
  • the application O2007015002 (Servier) describes Form IV of agomelatine
  • the application WO2007015004 describes Form V of agomelatine
  • the application WO2009095555 (Servier) describes Form VI of agomelatine
  • WO2011006387 Zhejiang Huahai Pharmaceutical Co., Ltd. describes Forms A, B and C of agomelatine.
  • Form II is the most stable one.
  • the other form or forms undergo transformation to the thermodynamically more stable Form II sooner or later.
  • Agomelatine is marketed in two products (Valdoxan and Thymanax, both of the 25 mg strength) of the company Sender, In these products agomelatine is present in the polymorphic Form ⁇ .
  • the authors of the invention have finally succeeded in finding the parameters that influence the resulting state of the material - whether it will have the form of a solid solution or solid dispersion not only immediately after the production, but also after processing into a pharmaceutical formulation throughout the stability testing period.
  • the present invention provides biologically available pharmaceutical compositions containing a thermo dynamically stable solid solution of agomelatine that ensure uniform releasing of agomelatine, guarantee a suitable dissolution profile and do not exhibit undesired recrystallization of agomelatine.
  • the invention provides a thermodynamically stable solid solution of agomelatine for use in a pharmaceutical formulation with the concentration of agomelatine in a polymeric carrier of up to 45% by weight, related to the weight of the solid solution, the particle size distribution of which after grinding is such that at most 60% by weight of particles are smaller than 0.1 mm.
  • the polymeric carrier used is a copolymer of polyvinylpyrrolidone with polyvinyl acetate (copovidone) in the weight ratio of 3:2 (Kollidon VA64).
  • a pharmaceutical composition containing this stable solid solution of agomelatine and non-hygroscopic pharmaceutically acceptable auxiliary substances with a low content of water.
  • the invention provides thermodynamically stable solid solutions of agomelatine for use in a pharmaceutical formulation with the concentration of agomelatine in a polymeric carrier of up to 45%» by weight, related to the weight of the solid solution, the particle size distribution of which after grinding is such that at most 60% by weight of particles are smaller than 0.1 mm, the polymeric carrier used being a copolymer of polyvinylpyrroUdone with polyvinyl acetate (copovidone) in the weight ratio of 3:2 (Kollidon VA64).
  • Other objects of this invention are pharmaceutical formulations containing said solid solution, which have the advantage in a faster and better solubility than that of a reference agomelatine formulation containing agomelatine particles (see Figure 10).
  • compositions containing the solid solution of agomelatine and the polymeric carrier in accordance with the present invention dissolve more quickly and better than the reference agomelatine preparation.
  • Parameters that are essential for achieving the technical effect of the invention include the type of the polymeric carrier, the concentration of agomelatine in said polymeric carrier and the particle size of the ground solid solution.
  • those parameters that have proved to be irrelevant for achievement of the technical effect of the invention include, e.g., the process temperature (virtually any melting temperature can be used in the range where reliable melting of the active substance and the polymer occurs and where the active substance is not subject to degradation at the same time), cooling rate, type of equipment for the preparation of the solid solution, grinding method of the solid solution (three device types were tested) etc.
  • a “solid solution” means a chemically and physically homogeneous amorphous material in which the molecules of the dissolved substance are homogeneously dispersed among the molecules of the carrier substance (the substance forrning the matrix of the solid solution) and in which no particles of the dissolved substance are detectable by any method known from the state of the art (e.g. an optical and electron microscope, FTIR microscopy, X-ray analysis, NMR).
  • a “solid dispersion” means a chemically and physically non-homogeneous material in which particles of the dissolved substance are detectable by a method known from the state of the art (e.g. an optical and electron microscope, FTIR microscopy, X-ray analysis, NMR).
  • the concentration of agomelatine in the solid solution in accordance with the invention which consists of agomelatine dissolved in a polymeric carrier, can be up to 45% by weight, conveniently 15 to 30% by weight, related to the weight of the solid solution.
  • the concentration of agomelatine in the solid solution is 15% by weight, related to the weight of the solid solution. In another preferred embodiment the concentration of agomelatine in the solid solution is 30% by weight, related to the weight of the solid solution.
  • the ratio of agomelatine to the polymeric carrier in the solid solution in accordance with the invention is lower than 1 : 1.2 (by weight), conveniently from 1 : 1.2 to 1 : 5.7 (by weight).
  • Polymeric carrier The polymeric carriers mentioned in the BASF document as the preferred ones were tested, i.e. Kollidon VA-64 (copolymer of polyvinylpyrrolidone with polyvinyl acetate (copovidone) in the weight ratio of 3:2), Soluplus (copolymer of polyvinyl caprolactam, polyvinyl acetate and polyethylene glycol) and Kollidon 30 (polyvinylpyrrolidone with the molecular weight characterized by the K 30 value).
  • Kollidon 30 polyvinylpyrrolidone with the molecular weight characterized by the K 30 value
  • the use of Kollidon 30 has proved to be possible, but inconvenient.
  • the glass transition temperature (Tg) of Kollidon 30 is 149°C and its working temperature is even 20 °C higher, while the melting temperature of agomelatine varies around 100°C.
  • An optimal condition for the preparation of solid solutions is that the active substance and the polymeric carrier have similar melting temperatures, which is not fulfilled here, but in spite of this a solid solution of agomelatine could be prepared.
  • the higher melting temperature of Kollidon 30 means higher energy costs and therefore no more stability or dissolution tests were carried out.
  • Soluplus has turned out to be absolutely unsuitable for preparation of a solid solution of agomelatine.
  • copolymer of polyvinyl caprolactam, polyvinyl acetate and polyethylene glycol (Soluplus) was used, crystalline Form II of agomelatine was always at least partly detected in the extrudate, and in the final dosage form (coated tablets) crystalline Form II was detected immediately after the production (see comparative Example 3). With this polymer we did not manage to find conditions under which it would be possible to prepare a stable solid solution without admixed recrystallized dispersed particles of agomelatine.
  • a preferred polymeric carrier of this technical solution is the copolymer of polyvinylpyrrolidone with polyvinyl acetate (Kollidon VA64).
  • Kollidon VA64 resulted in production of stable forms of both the extrudate with a rougher particle size and the extrudate after grinding to a fine particle size, as well as to the final dosage form after production and during storage of packed tablets for 1 month at 40°C and the relative humidity of 75%.
  • this is confirmation of absence of any crystalline form in the sample.
  • compositions containing a solid solution of agomelatine and pharmaceutically acceptable auxiliary substances e.g., fillers, disintegrants, binders and/or lubricants.
  • auxiliary substances e.g., fillers, disintegrants, binders and/or lubricants.
  • Preferred auxiliary substances are those that have a low content of free water (up to 7% by weight) and are non-hygroscopic.
  • Microcrystalline cellulose anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, lactose monohydrate, mannitol and/or sorbitol can be used as fillers.
  • Microcrystalline cellulose is preferred, especially microcrystalline cellulose with a water content of max. 1.5% by weight (e.g. type Avicel ⁇ 2).
  • Crosspovidone, low substituted hydroxypropyl cellulose and/or colloidal silicon dioxide can be used as disintegrants.
  • Crosspovidone and silicon dioxide are convenient and a combination of these two disintegrants is especially preferred.
  • Povidone, copovidone, hydroxypropyl cellulose and/or hydroxyethyl cellulose can be used as binders.
  • Magnesium stearate, calcium stearate, stearic acid and/or sodium stearyl fumarate can be used as lubricants.
  • a preferred solution includes the use of a combination of magnesium stearate and stearic acid.
  • Pharmaceutical formulations can be prepared in any commonly used form for oral administration, e.g., in the form of capsules, tablets or coated tablets, and can be packed in, e.g., vials or blister packs of a foil containing a PVC layer, PE layer and PVDC layer sealed with an aluminum foil (called PVC/PE/PVDC///ALU blisters) or in blister packs of an aluminum foil closed with an aluminum foil (called ALU// ALU blisters), in a normal or inert atmosphere.
  • the normal atmosphere means air and an inert atmosphere means a gas with oxygen content lower than 21% by vol.
  • An inert atmosphere conveniently consists of at least 95% by volume of nitrogen or 95% by volume of argon.
  • the solid solutions of agomelatine and a polymeric carrier in accordance with the invention can be prepared using the hot melt extrusion (HME) technology.
  • HME hot melt extrusion
  • agomelatine of the crystalline Form I is used.
  • the process temperature must not be too high to avoid chemical decomposition of the active substance, but sufficiently high to produce a clear solution of the active substance in the polymeric carrier.
  • extrudate After cooling and solidification the obtained extrudate is ground with a rotating knife or other technique into small pieces and is ready for further processing.
  • the production of extrudate has been verified in two types of extruders (Thermofisher, ThreeTec). The hourly quantity of produced extrudate has been tested to be up to 1 kg h and the extruder torque was 35-125 N.m.
  • the resulting solid solution can be further used for the production of a pharmaceutical composition.
  • any solvent e.g. water or ethanol
  • these include direct tabletting method or dry granulation method.
  • Direct tabletting represents a technological process wherein auxiliary substances are gradually, in multiple steps, sieved and mixed with the extrudate containing agomelatine in such a way that a sufficiently homogeneous mixture of substances for tableting results.
  • the cores are coated with a suspension consisting of common excipients.
  • the direct tabletting process is convenient for its simplicity.
  • Dry granulation may be an alternative method.
  • Compaction means a production method wherein the extrudate containing agomelatine and other excipients are homogenized in one or more production steps, followed by compressing a band of compact material by the effect of pressure in a compactor, which band is subsequently ground in a sieving device to a defined particle size depending on the mesh size.
  • the resulting granulate is either used directly to produce tablets, or one or more excipients are admixed and then it is used for the production of cores or tablets.
  • the cores are coated with a suspension consisting of common excipients.
  • the next production steps include tabletting and then coating and adjusting of tablets.
  • Fig. 1 XPRD analysis— confirmation of absence of the crystalline form of agomelatine in the extrudate of Example 1 (1 - roughly ground extrudate, 2 - finely ground, 3 - pure polymer Kollidon VA64, 4 - comparative: agomelatme of crystalline Form I)
  • Fig. 2 XPRD analysis - confirmation of absence of the crystalline form of agomelatine in cores made from the extrudate of Example 1 (1 - finely ground extrudate, 2 - cores made from this extrudate, 3 - verification of presence of magnesium stearate in the cores)
  • Fig. 3 XPRD analysis - confirmation of absence of the crystalline form of agomelatine in the extrudate from of 2 (1 - roughly ground extrudate, 2 - finely ground, 3 - comparative: agomelatine of crystalline Form II)
  • Fig. 4 XPRD analysis - confirmation of absence of the crystalline form of agomelatine in cores made from the extrudate of Example 2 (1 - finely ground extrudate, 2 - cores made from this extrudate, 3 - verification of presence of magnesium stearate, 4 - verification of presence of stearic acid in the cores)
  • Fig. 5 XPRD analysis - confirmation of absence of the crystalline form of agomelatine in the extrudate of Example 3 (1 -finely ground extrudate, 2 - pure polymer Kollidon VA64, 3 - comparative: agomelatine of crystalline Form I)
  • Fig. 6 XPRD analysis - confirmation of absence of the crystalline form of agomelatine in the extrudate of Example 4 (1 -finely ground extrudate, 2 - pure polymer Kollidon VA64, 3 - comparative: agomelatine of crystalline Form I)
  • Fig. 7 XPRD analysis - confirmation of absence of the crystalline form of agomelatine in the extrudate of Example 5 (1 - finely ground extrudate, 2 - comparative: agomelatine of crystalline Form II)
  • Fig. 8 XPRD analysis - confirmation of absence of the crystalline form of agomelatine in the extrudate of Example 6 (1 - finely ground extrudate, 2 - comparative: agomelatine of crystalline Form II)
  • Fig. 9 XPRD analysis - confirmation of presence of a mixture of crystalline Form II in the finely ground extrudate in Example 7 (1 - roughly ground extrudate, 2 - finely ground extrudate, 3 - comparative: agomelatine of crystalline Form II)
  • Fig. 10 Dissolution profiles
  • batch 200511 - Example 2 and batch 230611 - Example 1 to an even higher extent represent solid solutions exhibiting faster dissolution profiles than the reference product; on the other hand, batch 210511 - Example 7 - represents a solid dispersion and shows a considerable deceleration of the dissolution profile as compared to the reference product)
  • Agomelatine and Kollidon VA64 in the weight ratio of 15 : 85 are sieved through a 1.0 mm sieve and subsequently are homogenized in a stainless-steel container for 10 min.
  • the resulting mixture is poured into the reservoir of a POLYLAB OS Thermofisher hot melt extruder.
  • the mixture is continuously dosed to a worm transporter, where it gradually passes from the filling section through heated sections, where mixing, compression and melting of the polymer takes place.
  • the process temperature is 140°C.
  • the melted mixture is extruded through openings (of a matrix) out of the extruder. After cooling with air and solidification, the extrudate is ground with the use of rotating knives (rough grinding).
  • the resulting roughly ground extrudate is further refined to the defined particle size in the next grinder; see Example 1 - fine grinding.
  • the finely ground extrudate is used for the next production step, where auxiliary substances are gradually sieved in several steps (through a 1.0mm sieve) and mixed with the extrudate containing agomelatine in such a way that a sufficiently homogeneous mixture of substances for tableting results.
  • the cores are coated with a suspension consisting of common excipients.
  • Example 2 The same procedure as in Example 1 is followed. The only difference is in the composition- Agomelatine and Kollidon VA64 in the weight ratio of 30 : 70. The process temperature is 120°C.
  • Example 1 or 2 The same procedure as in Example 1 or 2 is followed.
  • the composition is the same as in Example 2 - Agomelatine and Kollidon VA64 in the weight ratio of 30 : 70;the process temperature is 135°C.
  • the only difference is in the particle size of the ground extrudate - grinding to finer particles than in Example 1 or 2.
  • Example 1 or 2 The same procedure as in Example 1 or 2 is followed. The only difference is the composition - Agomelatine and Kollidon VA64 in the weight ratio of 45 : 55. The process temperature is 120°C.
  • Example 2 The same procedure as in Example 1 or 2 is followed.
  • the composition is the same as in Example 2 - Agomelatine and Kollidon VA64 in the weight ratio of 30 : 70.
  • the process temperature is 120°C.
  • the only difference is in the particle size of the ground extrudate - grinding to very fine particles, 77% of weight of extrudate particles are smaller than 0.1 mm.
  • Composition of the product - core
  • Example 2 The same procedure as in Example 1 or 2 is followed. The only difference is in the composition- Agomelatine and Kollidon VA64 in the weight ratio of 50 : 50 - see Example 2. The process temperature is 120°C.
  • Admixed crystalline Form II of agomelatine was detected in the ground extrudate in accordance with Example 6 (see Fig. 8). At the concentration of 50% of agomelatine in the extrudate absence of the crystalline form of agomelatine in the extrudate cannot be achieved. Due to unsuitable polymorphy the dissolution profile was not measured.
  • EXAMPLE 7 - COMPARATIVE Agomelatine and Soluplus in the weight ratio of 30 : 70 are sieved through a 1.0 mm sieve and subsequently homogenized in a stainless-steel container for 10 min.
  • the resulting mixture is poured into the reservoir of a POLYLAB OS Thermofisher hot melt extruder.
  • the mixture is continuously dosed to a worm transporter, where it gradually passes from the filling section through heated sections, where mixing, compression and melting of the polymer takes place.
  • the process temperature is 120°C.
  • the melted mixture is extruded through openings (of a matrix) out of the extruder.
  • the extrudate is ground with the use of rotating knives.
  • the resulting roughly ground extrudate is further refined in the next grinder to the defined particle size, see Example 1 - fine grinding.
  • the finely ground extrudate is used for the next production step, where auxiliary substances are gradually sieved (through a 1.0mm sieve) in several steps and mixed with the extrudate containing agomelatine in such a way that a sufficiently homogeneous mixture of substances for tableting results.
  • the cores are coated with suspension consisting of common excipients, see Example 1.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une solution d'agomélatine solide et thermodynamiquement stable, contenant de l'agomélatine dissoute dans un support polymère qui est un copolymère de polyvinylpyrrolidone contenant de l'acétate de polyvinyle selon un rapport pondéral de 3:2 (Kollidon VA64), des procédés de préparation de ladite solution et des compositions pharmaceutiques contenant l'agomélatine (N-[2-(7-méthoxy-1-naphtyl)éthyle]-acétamide) de formule (I), et son procédé de fabrication.
PCT/CZ2014/000088 2013-08-13 2014-08-13 Solution d'agomélatine solide et thermodynamiquement stable destinée à être utilisée dans une préparation pharmaceutique WO2015021949A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZPV2013-621 2013-08-13
CZ2013-621A CZ2013621A3 (cs) 2013-08-13 2013-08-13 Termodynamicky stabilní tuhý roztok agomelatinu pro použití ve farmaceutické formulaci

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WO2015021949A1 true WO2015021949A1 (fr) 2015-02-19

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Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0447285A1 (fr) 1990-02-27 1991-09-18 Adir Et Compagnie Nouveaux dérivés à structure naphtalénique, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
WO2005077887A1 (fr) 2004-02-13 2005-08-25 Les Laboratoires Servier Nouveau procede de synthese et nouvelle forme cristalline de l’agomelatine ainsi que les compositions pharmaceutiques qui la contiennent
WO2007015002A2 (fr) 2005-08-03 2007-02-08 Les Laboratoires Servier Nouvelle forme cristalline iv de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent
WO2007015003A2 (fr) 2005-08-03 2007-02-08 Les Laboratoires Servier Nouvelle forme cristalline iii de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent
WO2007015004A2 (fr) 2005-08-03 2007-02-08 Les Laboratoires Servier Nouvelle forme cristalline v de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent
WO2009095555A1 (fr) 2007-11-09 2009-08-06 Les Laboratoires Servier Nouvelle forme cristalline vi de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent
WO2011006387A1 (fr) 2009-07-11 2011-01-20 浙江华海药业股份有限公司 Procédé pour la préparation d'agomélatine, cristaux d'agomélatine et leur procédé de préparation
WO2012093402A1 (fr) * 2011-01-04 2012-07-12 Symed Labs Limited Procédés pour la préparation de n-[2-(7-méthoxy-1-naphtyléthyl]acétamide
CN102670514A (zh) * 2012-04-29 2012-09-19 浙江华海药业股份有限公司 阿戈美拉汀固体制剂
WO2012130837A1 (fr) * 2011-03-28 2012-10-04 Ratiopharm Gmbh Agomélatine solide sous une forme non cristalline
EP2520288A1 (fr) * 2009-12-29 2012-11-07 Shanghai Zhongxi Pharmaceutical Company Procédé de production d'une préparation solide et préparation produite par ledit procédé

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0447285A1 (fr) 1990-02-27 1991-09-18 Adir Et Compagnie Nouveaux dérivés à structure naphtalénique, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
WO2005077887A1 (fr) 2004-02-13 2005-08-25 Les Laboratoires Servier Nouveau procede de synthese et nouvelle forme cristalline de l’agomelatine ainsi que les compositions pharmaceutiques qui la contiennent
WO2007015002A2 (fr) 2005-08-03 2007-02-08 Les Laboratoires Servier Nouvelle forme cristalline iv de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent
WO2007015003A2 (fr) 2005-08-03 2007-02-08 Les Laboratoires Servier Nouvelle forme cristalline iii de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent
WO2007015004A2 (fr) 2005-08-03 2007-02-08 Les Laboratoires Servier Nouvelle forme cristalline v de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent
WO2009095555A1 (fr) 2007-11-09 2009-08-06 Les Laboratoires Servier Nouvelle forme cristalline vi de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent
WO2011006387A1 (fr) 2009-07-11 2011-01-20 浙江华海药业股份有限公司 Procédé pour la préparation d'agomélatine, cristaux d'agomélatine et leur procédé de préparation
EP2520288A1 (fr) * 2009-12-29 2012-11-07 Shanghai Zhongxi Pharmaceutical Company Procédé de production d'une préparation solide et préparation produite par ledit procédé
WO2012093402A1 (fr) * 2011-01-04 2012-07-12 Symed Labs Limited Procédés pour la préparation de n-[2-(7-méthoxy-1-naphtyléthyl]acétamide
WO2012130837A1 (fr) * 2011-03-28 2012-10-04 Ratiopharm Gmbh Agomélatine solide sous une forme non cristalline
CN102670514A (zh) * 2012-04-29 2012-09-19 浙江华海药业股份有限公司 阿戈美拉汀固体制剂

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