EP2276466A1 - Granulés contenant de l'oxalate d'escitalopram - Google Patents

Granulés contenant de l'oxalate d'escitalopram

Info

Publication number
EP2276466A1
EP2276466A1 EP09741868A EP09741868A EP2276466A1 EP 2276466 A1 EP2276466 A1 EP 2276466A1 EP 09741868 A EP09741868 A EP 09741868A EP 09741868 A EP09741868 A EP 09741868A EP 2276466 A1 EP2276466 A1 EP 2276466A1
Authority
EP
European Patent Office
Prior art keywords
granulate
filler
tablet
granulate according
escitalopram
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP09741868A
Other languages
German (de)
English (en)
Inventor
Antje Lipsdorf
Alexandra Neumüller
Claudia Wolf
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hexal AG
Original Assignee
Hexal AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hexal AG filed Critical Hexal AG
Priority to EP09741868A priority Critical patent/EP2276466A1/fr
Publication of EP2276466A1 publication Critical patent/EP2276466A1/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants

Definitions

  • Granulate comprising escitalopram oxalate
  • the invention relates to a granulate comprising escitalopram oxalate having a particular, small average particle size and at least one filler.
  • the invention further relates to a method of producing that granulate and also to a tablet or capsule comprising that granulate and/or obtained by compressing that granulate to form a tablet or by filling that granulate into a capsule shell.
  • the invention relates to the use of that granulate and/or tablet or capsule in the treatment or prevention of a disorder from the spectrum of depressive disorders .
  • Citalopram 1- [3- (dimethylamino) propyl] -1- (4 -fluorophenyl) - 1, 3-dihydroisobenzofuran-5-carbonitrile, was first disclosed in DE 2 657 013 and US 4,136,193. It belongs to the class of selective serotonin reuptake inhibitors (SSRIs) , which selectively inhibit the reuptake of serotonin into nerve cells from the synaptic cleft. Citalopram is therefore mainly used as an antidepressant and as an anxiolytic. The average daily dose is 20 mg . Citalopram is marketed in the form of the hydrobromide salts and hydrochloride salts.
  • escitalopram instead of citalopram it is accordingly possible not only for the dose required for the pharmacological effect to be substantially reduced but also for the undesirable side-effects caused by (R) -citalopram to be avoided.
  • escitalopram is mainly used as an antidepressant and as an anxiolytic.
  • the average daily dose is 10 mg.
  • Escitalopram is marketed in the form of the oxalate salt.
  • WO 03/011278 Al there is described as a pharmaceutical dosage form a tablet which was obtained by direct compression of escitalopram oxalate together with customary pharmaceutical excipients. Because escitalopram oxalate can undergo direct compression only from a particular average particle size upwards, there were used in the course thereof crystalline particles of escitalopram oxalate having an average particle size of at least 40 ⁇ m, preferably from 50 to 200 ⁇ m, and in the disclosed example 163 ⁇ m. These particles were obtained by means of a specific crystallisation process, which is also described in WO 03/011278 Al.
  • escitalopram oxalate When escitalopram oxalate is used in the form of large crystalline particles, the bioavailability is impaired especially as a result of the fact that the dissolution and, therefore, the release of the active ingredient is delayed, which can result in slower active ingredient uptake in the body and, therefore, in a later onset of the desired pharmacological effect .
  • This is also relevant to escitalopram, notwithstanding the fact that escitalopram, like all SSRIs, develops its antidepressant action fully only after some weeks, because the action of escitalopram, especially its anxiolytic action, starts quickly after absorption into the body.
  • the present inventors have discovered that these problems of non-uniform active ingredient distribution and of impaired bioavailability can be avoided by using small and/or fine active ingredient particles which, by means of granulation, are brought into a state in which they can be compressed to form a tablet or filled into a capsule shell.
  • the problem of the present invention is to develop a pharmaceutical dosage form for escitalopram oxalate in which both the active ingredient is homogeneously distributed and therefore has greater bioavailability and also impurities arising in the course of formulation are minimised.
  • the present invention relates to a granulate which comprises escitalopram oxalate having an average particle size of less than 100 ⁇ m and at least one filler.
  • the active ingredient designation "escitalopram oxalate” includes all compounds which include both escitalopram and also oxalate, especially salts having an equimolar ratio of escitalopram and oxalate, and also all hydrates, solvates and polymorphic forms thereof.
  • average particle size also referred to as average grain size or average grade size, describes the median of the particle size distribution, which distribution can be determined by means of laser diffraction at 1 bar dispersive pressure using, for example, a Sympatec Helos apparatus.
  • the escitalopram oxalate used has an average particle size of less than 100 ⁇ m, especially greater than 0.5 ⁇ m and less than 100 ⁇ m, preferably from 0.6 ⁇ m to 60 ⁇ m, more preferably from 0.6 ⁇ m to 40 ⁇ m, even more preferably from 0.6 ⁇ m to less than 40 ⁇ m, even more preferably from 0.6 ⁇ m to 30 ⁇ m, even more preferably from 0.6 ⁇ m to 20 ⁇ m, even more preferably from 0.6 ⁇ m to less than 20 ⁇ m, even more preferably from 0.7 ⁇ m to 15 ⁇ m, most preferably from 0.8 ⁇ m to 10 ⁇ m.
  • the inventors have established that, by appropriately selecting the filler in the material to be granulated, the formation of active ingredient degradation products during the granulation procedure and accordingly the presence of impurities in the granulate can be reduced.
  • suitable fillers include sugars and sugar alcohols such as, for example, lactose, sucrose, glucose and mannitol, macromolecular fillers such as, for example, starches, especially maize starch, rice starch, potato starch and wheat starch, and also inorganic fillers such as, for example, calcium phosphates.
  • the particle size of the filler should not be too large to ensure adequate homogeneity in the granulate according to the invention.
  • the average particle size of the filler is preferably not greater than 200 ⁇ m.
  • microcrystalline cellulose has been found to be less suitable as filler and accordingly in a particular embodiment of the present invention the granulate contains less than 10 % by weight microcrystalline cellulose, preferably less than 5 % by weight microcrystalline cellulose, more preferably less than 2 % by weight microcrystalline cellulose, even more preferably less than 1 % by weight microcrystalline cellulose, in each case based on the filler, and most preferably no microcrystalline cellulose.
  • filler mixtures are lactose.
  • the filler containing at least 50 % by weight lactose, more preferably at least 60 % by weight lactose, even more preferably at least 70 % by weight lactose, even more preferably at least 80 % by weight lactose and most preferably at least 90 % by weight lactose, in each case based on the filler.
  • the present invention relates also to methods of producing a granulate as described hereinbefore.
  • the above definitions and explanations also apply.
  • the granulate of the present invention can be obtained using various granulating techniques. These include both wet granulation and also dry granulation. In a preferred embodiment, wet granulation is used. This includes both paste granulation, with use of a binder, and also so called “crust granulation" (german:
  • wet granulation is employed with use of a binder.
  • a binder it has been found, surprisingly, that it is the selection of filler rather than the selection of binder that is decisive for avoiding the formation of active ingredient degradation products during the granulation procedure.
  • binder there may be used therefore any binder customary in the pharmaceutical sector, including, inter alia, sugars, especially sucrose, macromolecular binders such as, for example, starches, especially maize starch, rice starch, potato starch and wheat starch, gelatin, tragacanth, cellulose ethers, especially hydroxypropylcellulose, hydroxypropyl methylcellulose (HMPC) and carboxymethylcellulose sodium, and polyvinylpyrrolidones, also referred to as polyvidones or povidones, especially copovidones . Preference is given to using HPMC or copovidones as binder.
  • the binder is contained in the granulate according to the invention preferably in an amount of from 2 to 10 % by weight.
  • microcrystalline cellulose preferably less than 5 % by weight microcrystalline cellulose, more preferably less than 2 % by weight microcrystalline cellulose, even more preferably less than 1 % by weight microcrystalline cellulose, in each case based on the total amount of the filler, and most preferably no microcrystalline cellulose is present in the material being granulated.
  • the granulation is preferably carried out as wet granulation using a binder with subsequent fluidised-bed drying.
  • the wet granulation is preferably carried out in a mixing granulator (high-speed mixer) .
  • the active ingredient is pre-mixed with the filler or fillers in the granulator and subsequently granulated using the binder solution.
  • the binder may also be added to the pre-mix in dry powder form and granulation carried out using only the liquid (for example, water) .
  • the present invention relates also to pharmaceutical dosage forms for the granulate according to the invention.
  • Pharmaceutical dosage forms according to the invention that come into consideration are, especially, tablets and capsules.
  • the granulate according to the invention can itself also be used directly as a pharmaceutical dosage form according to the invention.
  • the pharmaceutical dosage forms according to the invention may furthermore comprise further customary pharmaceutical excipients, especially disintegrants or disintegration accelerators, dry binders, flow regulators, lubricants, antisticking agents, film-forming agents, plasticisers and/or pigments .
  • Any disintegrant customary in the pharmaceutical sector may be used as a disintegrant .
  • the disintegrants are added preferably after granulation and are then a constituent of the external phase of the granulate for improving dissolution of the granulate in the body.
  • starches and starch derivatives especially maize starch, rice starch, potato starch and wheat starch, polyvinylpyrrolidone, especially cross-linked polyvinylpyrrolidone, and carboxymethylcellulose sodium or croscarmellose sodium, especially low-substituted carboxymethylcellulose sodium.
  • croscarmellose sodium is contained in the granulate according to the invention preferably in an amount of from 3 to 6 % by weight .
  • dry binder customary in the pharmaceutical sector may be used as a dry binder.
  • the dry binders are added preferably after granulation and are then a constituent of the external phase of the granulate for improving the compressibility of the granulate. They include, inter alia, mannitol, cellulose, especially microcrystalline cellulose, and calcium phosphates. Preference is given to the use of microcrystalline cellulose as dry binder.
  • Any flow regulator customary in the pharmaceutical sector may be used as a flow regulator.
  • the flow regulators are added preferably after granulation and are then a constituent of the external phase of the granulate for optimising the flow properties of the granulate. Preference is given to the use of colloidal silica as flow regulator.
  • the flow regulator is contained in the granulate according to the invention preferably in an amount of from 0.1 to 2 % by weight .
  • Any lubricant customary in the pharmaceutical sector may be used as a lubricant .
  • the lubricants are added preferably after granulation and are then a constituent of the external phase of the granulate for reducing the friction between the granulate being tabletted and the tabletting tool.
  • fatty acids especially stearic acid, salts of fatty acids with divalent metals, especially magnesium stearate, calcium arachinate, fatty alcohols, especially stearyl alcohol, sodium stearyl fumarate, polyethylene glycols and talc.
  • fatty acids especially stearic acid, salts of fatty acids with divalent metals, especially magnesium stearate, calcium arachinate, fatty alcohols, especially stearyl alcohol, sodium stearyl fumarate, polyethylene glycols and talc.
  • fatty alcohols especially stearyl alcohol, sodium stearyl fumarate, polyethylene glycols and talc.
  • stearyl alcohol especially stearyl alcohol, sodium stearyl fumarate, polyethylene glycols and talc.
  • Film-forming agents include, inter alia, cellulose derivatives, especially methylcellulose, hydroxypropyl methylcellulose, also referred to as hypromellose, hydroxypropylcellulose, hydroxyethyl- cellulose, carboxymethylcellulose sodium, ethylcellulose, cellulose acetate phthalate and hydroxypropyl methylcellulose phthalate, polyacrylates and polymethacrylates, especially Eudragit E, NE, L, S, RL and RS, vinyl polymers, especially polyvinylpyrrolidone and polyvinyl acetate phthalate, and natural film-forming agents, especially shellac. Preference is given to the use of hypromellose as film-forming agent.
  • Any antisticking agent customary in the pharmaceutical sector may be used as an antisticking agent .
  • the antisticking agents are added preferably during film- forming and are then a constituent of the film for preventing the tablets from adhering to one another during coating. Preference is given to the use of talc as antisticking agent.
  • Any plasticiser customary in the pharmaceutical sector may be used as a plasticiser.
  • the plasticisers are added preferably during film-forming and are then a constituent of the film. Preference is given to the use of polyethylene glycols, also referred to as macrogols, as plasticiser.
  • Any pigment customary in the pharmaceutical sector may be used as a pigment.
  • the pigments are added preferably during film- forming and are then a constituent of the film. Preference is given to the use of titanium oxide as pigment.
  • the pharmaceutical dosage forms according to the invention comprise the granulate according to the invention.
  • a tablet according to the invention can be obtained especially by compressing a granulate according to the invention to form the tablet.
  • a capsule according to the invention can be obtained by filling a granulate according to the invention into a capsule shell .
  • tablets there can be produced simple tablets, lozenges, chewable tablets, sublingual tablets, effervescent tablets, dispersible tablets, multilayer tablets, enteric-coated tablets or matrix tablets. Compression to form tablets can be carried out by the customary methods for tablet compression, especially using eccentric presses or rotary presses. Special preference is given to the production of film-coated tablets.
  • capsules there can be produced hard gelatin capsules. Filling of the capsule shells can be carried out by the customary methods for capsule filling.
  • the amount of escitalopram oxalate used in the pharmaceutical dosage form according to the invention is governed by the desired pharmacological effects and furthermore depends especially on the age, sex and weight of the person to be treated. Usual amounts of escitalopram oxalate in the pharmaceutical dosage form according to the invention are, for example, 2.5 mg, 5 mg, 10 mg or 20 rag, in each case based on escitalopram.
  • the present invention relates also to the use of a pharmaceutical dosage form according to the invention, especially a granulate according to the invention or a tablet or capsule according to the invention, in the treatment or prevention of a disorder from the spectrum of depressive disorders, especially in patients with inhibited-depressive syndrome.
  • a pharmaceutical dosage form according to the invention especially a granulate according to the invention or a tablet or capsule according to the invention.
  • Use in the treatment or prevention of panic disorders and anxiety disorders, especially social phobia and agoraphobia is also possible with a pharmaceutical dosage form according to the invention.
  • Escitalopram oxalate was used in the following examples of particle size distribution:
  • D (0.1), D (0.5) and D (0.9) denote the particle sizes up to which cumulatively 10 %, 50 % and 90 %, respectively, of particles in the particle size distribution were found to lie.
  • D (0.1) and D (0.9) accordingly correspond to the 0.1-quantile and 0.9-quantile, respectively, of the particle size distribution;
  • D (0.5) corresponds to the median of the particle size distribution.
  • Example 1 Example 2 (i) 0.32 % 0.08 % (ii) 0.55 % 0.15 %

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur des granulés contenant de l'oxalate d'escitalopram présentant une dimension moyenne de particule inférieure à 100 µm et au moins une charge. L'invention porte en outre sur un procédé de fabrication de ces granulés ainsi que sur des comprimés ou capsules contenant ces granulés et/ou obtenus par compression de ces granulés pour former un comprimé ou par remplissage de coques de capsules par ces granulés. Enfin, l'invention porte sur l'utilisation de ces granulés et/ou de ces comprimés ou capsules dans le traitement ou la prévention d'un trouble appartenant au spectre des troubles dépressifs.
EP09741868A 2008-05-07 2009-05-05 Granulés contenant de l'oxalate d'escitalopram Withdrawn EP2276466A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP09741868A EP2276466A1 (fr) 2008-05-07 2009-05-05 Granulés contenant de l'oxalate d'escitalopram

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP08008614A EP2116231A1 (fr) 2008-05-07 2008-05-07 Granulé comprenant de l'oxalate d'escitalopram
EP09741868A EP2276466A1 (fr) 2008-05-07 2009-05-05 Granulés contenant de l'oxalate d'escitalopram
PCT/EP2009/003214 WO2009135649A1 (fr) 2008-05-07 2009-05-05 Granulés contenant de l'oxalate d'escitalopram

Publications (1)

Publication Number Publication Date
EP2276466A1 true EP2276466A1 (fr) 2011-01-26

Family

ID=39731669

Family Applications (2)

Application Number Title Priority Date Filing Date
EP08008614A Withdrawn EP2116231A1 (fr) 2008-05-07 2008-05-07 Granulé comprenant de l'oxalate d'escitalopram
EP09741868A Withdrawn EP2276466A1 (fr) 2008-05-07 2009-05-05 Granulés contenant de l'oxalate d'escitalopram

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP08008614A Withdrawn EP2116231A1 (fr) 2008-05-07 2008-05-07 Granulé comprenant de l'oxalate d'escitalopram

Country Status (9)

Country Link
EP (2) EP2116231A1 (fr)
JP (1) JP5575114B2 (fr)
CN (1) CN102026626B (fr)
AU (1) AU2009243734B2 (fr)
BR (1) BRPI0912253A2 (fr)
CA (1) CA2722802C (fr)
EA (1) EA201001740A1 (fr)
WO (1) WO2009135649A1 (fr)
ZA (1) ZA201007554B (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITMI20120448A1 (it) 2012-01-30 2013-07-31 Carthesia Sas Composizione liofilizzata di escitalopram ossalato per somministrazione sublinguale
CN104523638B (zh) * 2014-11-28 2020-02-21 浙江华海药业股份有限公司 含有草酸艾司西酞普兰的片剂及其制备方法
WO2018190294A1 (fr) * 2017-04-10 2018-10-18 東和薬品株式会社 Composition médicinale comprenant de l'escitalopram
CN107441053A (zh) * 2017-06-21 2017-12-08 山东京卫制药有限公司 一种草酸艾司西酞普兰片的制备方法
JP7453859B2 (ja) 2020-06-22 2024-03-21 東和薬品株式会社 エスシタロプラム錠剤

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1526331A (en) 1976-01-14 1978-09-27 Kefalas As Phthalanes
GB8814057D0 (en) 1988-06-14 1988-07-20 Lundbeck & Co As H New enantiomers & their isolation
JP2005525993A (ja) 2001-07-31 2005-09-02 ハー・ルンドベック・アクチエゼルスカベット エスシタロプラムを含む結晶性組成物
EP1732514A1 (fr) * 2004-03-05 2006-12-20 H. Lundbeck A/S Composition cristalline contenant de l'oxalate d'escitalopram
WO2006123243A2 (fr) * 2005-05-20 2006-11-23 Aurobindo Pharma Limited Formes galeniques pharmaceutiques d'un antidepresseur
US8252336B2 (en) * 2006-10-20 2012-08-28 Ratiopharm Gmbh Escitalopram and solid pharmaceutical composition comprising the same

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2009135649A1 *

Also Published As

Publication number Publication date
JP2011520798A (ja) 2011-07-21
WO2009135649A1 (fr) 2009-11-12
ZA201007554B (en) 2012-01-25
AU2009243734A1 (en) 2009-11-12
BRPI0912253A2 (pt) 2015-10-06
CA2722802C (fr) 2016-06-07
EP2116231A1 (fr) 2009-11-11
CN102026626B (zh) 2013-01-09
CN102026626A (zh) 2011-04-20
EA201001740A1 (ru) 2011-06-30
AU2009243734B2 (en) 2014-02-27
CA2722802A1 (fr) 2009-11-12
JP5575114B2 (ja) 2014-08-20

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