WO2009066181A2 - Pastilles de chlorhydrate de duloxétine pour administration orale à libération retardée - Google Patents

Pastilles de chlorhydrate de duloxétine pour administration orale à libération retardée Download PDF

Info

Publication number
WO2009066181A2
WO2009066181A2 PCT/IB2008/003741 IB2008003741W WO2009066181A2 WO 2009066181 A2 WO2009066181 A2 WO 2009066181A2 IB 2008003741 W IB2008003741 W IB 2008003741W WO 2009066181 A2 WO2009066181 A2 WO 2009066181A2
Authority
WO
WIPO (PCT)
Prior art keywords
duloxetine hydrochloride
delayed
layer
release
pharmaceutically acceptable
Prior art date
Application number
PCT/IB2008/003741
Other languages
English (en)
Other versions
WO2009066181A3 (fr
Inventor
Sergio Lloret Perez
Agnes Fernandez Pena
Original Assignee
Combino Pharm, S.L.
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 Combino Pharm, S.L. filed Critical Combino Pharm, S.L.
Publication of WO2009066181A2 publication Critical patent/WO2009066181A2/fr
Publication of WO2009066181A3 publication Critical patent/WO2009066181A3/fr

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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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

  • the invention relates to oral delayed-release pellets of duloxetine hydrochloride.
  • the invention further includes processes for their preparation and utilization.
  • Duloxetine hydrochloride (chemical name: (+)-(5)-N-methyl- ⁇ -(l-naphthyloxy)-2- thiophenepropylamine hydrochloride) is a selective serotonin and norepinephrine reuptake inhibitor (SS ⁇ RI) for oral administration.
  • Duloxetine hydrochloride has the following formula:
  • duloxetine hydrochloride can exist in two enantiomeric forms (R and S), with the S form being the more commercially desirable enantiomer due to its pharmacological activity.
  • the term "duloxetine hydrochloride” as used herein will refer to the S enantiomeric form unless otherwise specified.
  • CymbaltaTM as capsules containing delayed-release pellets for oral administration for the treatment of major depressive disorder (MDD), for the management of neuropathic pain associated with diabetic peripheral neuropathy and for the treatment of generalized anxiety disorder (GAD).
  • MDD major depressive disorder
  • GAD generalized anxiety disorder
  • duloxetine hydrochloride has been approved by EMEA as hard gastroresistant capsules under the name AriclaimTM and YentreveTM for the treatment of moderate to severe Stress Urinary Incontinence (SUI) for women and under the name Cymbalta M and Xeristar for the treatment of major depressive episodes and for treatment of diabetic peripheral neuropathic pain in adults.
  • United States Patent No. 5,508,276 encompasses an enteric duloxetine pellet which necessarily contains a core that includes duloxetine hydrochloride and an enteric layer that includes hydroxypropylmethylcellulose acetate succinate (HPMCAS). Due to the fact that duloxetine hydrochloride exhibits instability in acidic conditions and that the HPMCAS enteric polymer has free acidic groups in the final composition, these pellets require a separating layer between duloxetine hydrochloride- containing core and the enteric layer in order to avoid the degradation of duloxetine hydrochloride. Therefore, the separating layer serves to avoid direct contact between duloxetine hydrochloride and the enteric layer, and consequently to avoid the undesired reaction between each other. Indeed, no additional functionality of this separating layer in the release of the drug is recognized.
  • HPMCAS hydroxypropylmethylcellulose acetate succinate
  • the invention provides new delayed-release duloxetine hydrochloride pellets containing: i. an inert core; ii. a first layer including duloxetine hydrochloride and optionally one or more pharmaceutically acceptable excipients; iii. an intermediate layer including at least one cellulosic derivative polymer and optionally one or more pharmaceutically acceptable excipients; and iv. an enteric layer including an enteric polymer and optionally one or more pharmaceutically acceptable excipients.
  • the invention provides a process for preparing the above- described delayed-release pellets of duloxetine hydrochloride.
  • the process includes: i. applying to inert cores a first layer including duloxetine hydrochloride and optionally one or more pharmaceutically acceptable excipients; ii. applying to the obtained duloxetine hydrochloride-containing cores an intermediate layer including at least one cellulosic derivative polymer and optionally one or more pharmaceutically acceptable excipients; and iii. applying an enteric layer including an enteric polymer and optionally one or more pharmaceutically acceptable excipients.
  • the invention includes the use of above-described capsules containing the enteric pellets of duloxetine hydrochloride according to the invention for the treatment of major depressive disorder (MDD), for the management of neuropathic pain associated with diabetic peripheral neuropathy, for the treatment of generalized anxiety disorder (GAD) and for the treatment of moderate to severe Stress Urinary Incontinence (SUI) for women.
  • MDD major depressive disorder
  • GAD generalized anxiety disorder
  • SUI moderate to severe Stress Urinary Incontinence
  • Inert cores are known and commonly used in pharmaceutical compositions and are also commercially available. These inert cores can be made from microcrystalline cellulose, mannitol or a mixture of sucrose and starch (commonly known as sugar spheres). The size range of these inert cores depends on the desired size of the final pellet.
  • Preferred inert cores are sugar spheres with a size from approximately 355 to approximately 500 micrometers.
  • the inert core is covered by a first layer containing duloxetine hydrochloride and optionally one or more pharmaceutically acceptable excipients.
  • a preferred pharmaceutically acceptable excipient is a polymer which allows the duloxetine hydrochloride to stick to the inert cores.
  • Preferred polymers include hydroxypropylmethylcellulose, methylcellulose, carboxymethylcellulose, polyvinylpirrolidone, xanthan gum acacia or gelatin.
  • a more preferred polymer is hydroxypropylmethylcellulose.
  • a preferred manner of coating the inert cores with the duloxetine hydrochloride is spraying a slurry suspension of duloxetine hydrochloride and the appropriate excipients in water.
  • coated cores can be made following this technique in a fluid bed dryer equipped with a
  • the preferred equipment is a fluid bed dryer equipped with a Wurster column.
  • this first layer can also be obtained by a "powder coating” process where the inert cores are moistened with a binder, duloxetine hydrochloride is added and mixed until homogeneous distribution, and the obtained cores are dried.
  • These coated cores could be made following this technique in a high shear granulator, in a non- perforated coating pan or in a fluidized bed dryer equipped with a rotary processor or with a rotating plate.
  • the intermediate layer includes a polymeric material.
  • the polymer used must be neutral.
  • the intermediate layer may also contain one or more pharmaceutically acceptable excipients.
  • a preferred neutral polymer is a cellulosic derivative polymer.
  • Preferred pharmaceutically acceptable excipients for the intermediate layer are sucrose and talc.
  • a preferred intermediate layer weight is from approximately 3% to approximately 60% of the weight of duloxetine hydrochloride-containing core (sugar spheres and duloxetine hydrochloride first layer).
  • a more preferred intermediate layer weight is from approximately 5% to approximately 6% of the weight of duloxetine hydrochloride- containing core (sugar spheres and duloxetine hydrochloride first layer).
  • the intermediate layer may be applied by spraying aqueous mixtures of the polymeric material with one or more pharmaceutically acceptable excipients.
  • a preferred method for applying this intermediate layer uses the fluidized bed dryer equipped with a Wurster column. Alternatively, a fluidized bed dryer equipped with a non-perforated coating pan could be used for applying this intermediate layer.
  • the enteric layer controls the place where the dissolution must be produced, i.e., the enteric formulation passes unchanged through the stomach of the patient, and the enteric layer is dissolved and allows delivery of the duloxetine hydrochloride when it leaves the stomach and enters into the small intestine.
  • an enteric layer includes a polymeric material.
  • the enteric layer also contains one or more pharmaceutically acceptable excipients.
  • a preferred enteric polymer is a vinyl derivative polymer, more preferred is a polyvinyl acetate phthalate (tradename SuretericTM).
  • a preferred pharmaceutically acceptable excipient with this enteric polymer is an antifoam excipient.
  • a preferred antifoam excipient is silicone, more preferred is simethicone (tradename SuretericTM antifoam emulsion).
  • enteric polymers include eudragit polymers.
  • a preferred eudragit polymer is an ethyl acrylate/methacrylic acid copolymer (1 :1) (tradename EudragitTM L30D55).
  • Preferred pharmaceutically acceptable excipients with this enteric polymer are triethyl citrate, talc and titanium dioxide. Further, it has been observed that if titanium dioxide is not used as at least one of the pharmaceutically acceptable excipients with this enteric polymer (i.e. EudragitTM L30D55), the resultant duloxetine pellets show a lower dissolution profile as compared to the pellets contained in the commercially available duloxetine capsules (i.e., Cymbalta®).
  • talc as a pharmaceutically acceptable excipient with this enteric polymer can be optional, since the resultant duloxetine pellets show a dissolution profile very similar to the pellets contained in the commercially available duloxetine capsules (i.e., Cymbalta®).
  • a preferred enteric layer weight is when there is from approximately 5% to approximately 55% in weight with respect to the total weight of the duloxetine hydrochloride containing core and the intermediate layer (sugar spheres, duloxetine first layer and second layer).
  • a more preferred enteric layer weight is when there is from approximately 38% to approximately 46% in weight with respect to the total weight of the duloxetine hydrochloride containing core and the intermediate layer (sugar spheres, duloxetine first layer and second layer).
  • the enteric layer may be obtained by spraying a suspension from enteric polymer with water, preferably, or organic solvents.
  • a preferred method for applying this layer uses a fluidized bed dryer equipped with a Wurster column.
  • a fluidized bed dryer equipped with a non- perforated coating pan could be used for applying this enteric layer.
  • the intermediate layer weight is from approximately 5% to approximately 6% in weight with respect to the duloxetine hydrochloride-containing core (sugar spheres and duloxetine hydrochloride first layer)
  • the enteric layer weight is from approximately 38% to approximately 46% in weight with respect to the duloxetine hydrochloride containing core and the intermediate layer (sugar spheres, duloxetine first layer and second layer)
  • the resultant duloxetine pellets show a dissolution profile very similar to the pellets contained in the commercially available duloxetine capsules (i.e.,
  • Example I purified water used during preparation and was then removed. As such, it is not present in the final pellets and is not included in the above list. [0030] The product of Example 1 was made by the following process: A. First Layer (Duloxetine Hydrochloride-Containing Cores)
  • step 3a Incorporate the duloxetine hydrochloride into the solution of step 2a with a helix stirrer and vortex formation. Stir until there is a homogeneous dispersion;
  • step 5b Coat the product of step 6a until final weight.
  • step 5c Pass the dispersion of step 3c through a 0.25mm sieve and maintain with agitation throughout the coating process;
  • Example 2 purified water used during preparation and was then removed. As such, it is not present in the final pellets and is not included in the above list. [0032] The product of Example 2 was made by the following process: A. First Layer (Duloxetine Hydrochloride-Containing Cores)
  • step 3a Incorporate the duloxetine hydrochloride into the solution of step 2a with a helix stirrer and vortex formation. Stir until homogeneous dispersion;
  • step 4a Introduce the sugar spheres into the Wurster column; 5a. Pass the dispersion of step 3a through a 0.5 mm sieve and maintain the dispersion with agitation throughout the coating process; and 6a. Coat the sugar spheres until final weight.
  • step 3b Dissolve the sucrose in the solution of step 2b.
  • step 4b Incorporate the talc into the solution of step 2b with a helix stirrer and vortex formation. Stir until there is a homogeneous dispersion and maintain the dispersion with agitation throughout the coating process;
  • step 5b Coat the product of step 6a until final weight.
  • step 3c Maintain the dispersion of step 2c under agitation with a helix stirrer for 15 minutes;
  • step 4c Pass the dispersion of step 3c through a 0.25 mm sieve;
  • step 5c Add the dispersion of step 4c onto the EudragitTM L30-D55. Maintain the solution with agitation for a minimum of 30 minutes and maintain with agitation throughout the coating process;
  • Example 3 **Added as EudragitTM L30D55 In Example 3, purified water used during the preparation and was removed. As such, it is not present in the final pellets and is not included in the above list.
  • the product of Example 3 was made by the following process:
  • step 3a Incorporate the duloxetine hydrochloride into the solution of step 2a with a helix stirrer and vortex formation. Stir until homogeneous dispersion;
  • step 5a Pass the dispersion of step 3a through a 0.5 mm sieve and maintain the dispersion with agitation throughout the coating process;
  • step 3b Dissolve the sucrose in the solution of step 2b.
  • step 4b Incorporate the talc into the solution of step 3b with a helix stirrer and vortex formation. Stir until homogeneous dispersion and maintain the dispersion with agitation throughout the coating process;
  • step 6a Coat the product of step 6a by means of spry-drying until final weight.
  • step 3c Pass the dispersion of step 2c through ultraturrax during 15 min;
  • step 4c Pass the dispersion of step 3c through a 0.25mm sieve; 5c. Add the dispersion of step 4c onto the EudragitTM L30-D55.
  • step 6c Coat the product of step 5b by means of spry-drying until final weight.
  • Example 3 The capsules of Example 3 and commercially available Duloxetine capsules (i.e., Cymbalta ® 60mg) were tested for in vitro drug release in 750 mL of HCl 0.1 N and 250 mL OfNa 3 PO 4 0.2 M, having a pH of approximately 6.8 [see USP ⁇ 724> Delayed-Release (Enteric coated) Articles-General Drug Release Standard (Method A) ; current edition]. A USP-I apparatus with baskets speed at 100 rpm was used for the study. The dissolution results are reported in Table 1 (below) and illustrated in Graph 1 (below):

Landscapes

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

Abstract

L'invention concerne des pastilles de chlorhydrate de duloxétine pour administration orale à libération retardée. L'invention concerne en outre des procédés permettant leur préparation et leur utilisation.
PCT/IB2008/003741 2007-07-09 2008-07-09 Pastilles de chlorhydrate de duloxétine pour administration orale à libération retardée WO2009066181A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US92969707P 2007-07-09 2007-07-09
US60/929,697 2007-07-09

Publications (2)

Publication Number Publication Date
WO2009066181A2 true WO2009066181A2 (fr) 2009-05-28
WO2009066181A3 WO2009066181A3 (fr) 2009-08-20

Family

ID=40667910

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2008/003741 WO2009066181A2 (fr) 2007-07-09 2008-07-09 Pastilles de chlorhydrate de duloxétine pour administration orale à libération retardée

Country Status (2)

Country Link
AR (1) AR067502A1 (fr)
WO (1) WO2009066181A2 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010037849A1 (fr) * 2008-10-02 2010-04-08 Laboratorios Del Dr. Esteve, S.A. Pastilles de duloxétine gastro-résistantes
WO2011039768A3 (fr) * 2009-09-17 2011-09-01 Cadila Healthcare Limited Compositions pharmaceutiques pour réduire une libération massive induite par l'alcool
WO2015025261A1 (fr) 2013-08-21 2015-02-26 Adamed Sp. Z O.O. Comprimé de duloxétine à enrobage entérique

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0693282A2 (fr) * 1994-07-18 1996-01-24 Eli Lilly And Company Pilules entériques contenant de la duloxétine
WO1997033880A1 (fr) * 1996-03-11 1997-09-18 Eli Lilly And Company Methodes de traitement ou de prevention de la cystite interstitielle
EP1640000A2 (fr) * 2002-11-27 2006-03-29 Boehringer Ingelheim International GmbH Composition pharmaceutique comprenant un agoniste de l'adrénocepteur béta-3 et un inhibiteur de la recapture de la sérotonine et/ou de la norépinéphrine
WO2007034503A2 (fr) * 2005-06-20 2007-03-29 Cadila Healthcare Limited Formulation galenique a liberation commandee de duloxetine
WO2007139886A2 (fr) * 2006-05-22 2007-12-06 Teva Pharmaceutical Industries Ltd. Formulations à libération retardée de chlorhydrate de duloxétine
EP1938840A1 (fr) * 2006-12-27 2008-07-02 LEK Pharmaceuticals D.D. Composition à base de Duletoxine
WO2008129501A2 (fr) * 2007-04-20 2008-10-30 Wockhardt Research Centre Compositions pharmaceutiques de duloxetine

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0693282A2 (fr) * 1994-07-18 1996-01-24 Eli Lilly And Company Pilules entériques contenant de la duloxétine
WO1997033880A1 (fr) * 1996-03-11 1997-09-18 Eli Lilly And Company Methodes de traitement ou de prevention de la cystite interstitielle
EP1640000A2 (fr) * 2002-11-27 2006-03-29 Boehringer Ingelheim International GmbH Composition pharmaceutique comprenant un agoniste de l'adrénocepteur béta-3 et un inhibiteur de la recapture de la sérotonine et/ou de la norépinéphrine
WO2007034503A2 (fr) * 2005-06-20 2007-03-29 Cadila Healthcare Limited Formulation galenique a liberation commandee de duloxetine
WO2007139886A2 (fr) * 2006-05-22 2007-12-06 Teva Pharmaceutical Industries Ltd. Formulations à libération retardée de chlorhydrate de duloxétine
EP1938840A1 (fr) * 2006-12-27 2008-07-02 LEK Pharmaceuticals D.D. Composition à base de Duletoxine
WO2008129501A2 (fr) * 2007-04-20 2008-10-30 Wockhardt Research Centre Compositions pharmaceutiques de duloxetine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JANSEN P J ET AL: "CHARACTERIZATION OF IMPURITIES FORMED BY INTERACTION OF DULOXETINE HCI WITH ENTERIC POLYMERS HYDROXYPROPYL METHYLCELLULOSE ACETATE SUCCINATE AND HYDROXYPROPYL METHYLCELLULOSE PHTHALATE" JOURNAL OF PHARMACEUTICAL SCIENCE, AMERICAN PHARMACEUTICAL ASSOCIATION, WASHINGTON, US, vol. 87, no. 1, 1 January 1998 (1998-01-01), pages 81-85, XP000891949 ISSN: 0022-3549 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010037849A1 (fr) * 2008-10-02 2010-04-08 Laboratorios Del Dr. Esteve, S.A. Pastilles de duloxétine gastro-résistantes
WO2011039768A3 (fr) * 2009-09-17 2011-09-01 Cadila Healthcare Limited Compositions pharmaceutiques pour réduire une libération massive induite par l'alcool
JP2013504562A (ja) * 2009-09-17 2013-02-07 カディラ・ヘルスケア・リミテッド アルコールで誘発される用量ダンピングを低減するための医薬組成物
WO2015025261A1 (fr) 2013-08-21 2015-02-26 Adamed Sp. Z O.O. Comprimé de duloxétine à enrobage entérique

Also Published As

Publication number Publication date
WO2009066181A3 (fr) 2009-08-20
AR067502A1 (es) 2009-10-14

Similar Documents

Publication Publication Date Title
US20090175935A1 (en) Pharmaceutical compositions of duloxetine
KR101873075B1 (ko) 하나 이상의 알긴산 염을 포함하는 위 내성 제약 또는 건강기능식품 제제
JP2002529401A (ja) 水溶性薬物の放出制御製剤
JP2002523443A (ja) オメプラゾール製剤
JP2009527554A (ja) コハク酸メトプロロールｅ．ｒ．の錠剤およびその調製方法
JP2009510027A (ja) ベンラファキシン塩酸塩の制御放出性の医薬組成物、及びその調製方法
RU2372893C2 (ru) Содержащий фармацевтический агент состав с покрытием
JP2010530868A (ja) デュロキセチン製剤
EP2289497A1 (fr) Administration à prise unique quotidienne de médicaments agissant sur le système nerveux central
US20080226711A1 (en) Pharmaceutical compositions of duloxetine
US20070092568A1 (en) Galantamine compositions
EP2099492B1 (fr) Composition a base de duloxetine
WO2010066268A1 (fr) Granules de tamsulosine pour une association à dose fixe
WO2009066181A2 (fr) Pastilles de chlorhydrate de duloxétine pour administration orale à libération retardée
US20090220593A1 (en) Extended release dosage forms of quetiapine
CA2645940A1 (fr) Formule a liberation controlee de tolterodine
US9498440B2 (en) Extended release pharmaceutical compositions
RU2727721C2 (ru) Фармацевтическая композиция с замедленным высвобождением, содержащая ривастигмин
EP1938840A1 (fr) Composition à base de Duletoxine
WO2004066982A1 (fr) Compositions orales stables de benzimidazole et leurs procedes de preparation
KR20130071430A (ko) 둘록세틴의 경구 약제학적 조성물
EP2133072A1 (fr) Compositions orales pharmaceutiques gastro-résistantes comportant du duloxétine ou ses dérivés pharmaceutiques acceptables
US20080081067A1 (en) Sustained release pharmaceutical compositions of venlafaxine and process for preparation thereof
WO2005051362A2 (fr) Compositions stables de benzimidazole a administration orale et leurs procedes de preparation
JP2005200399A (ja) 塩酸タムスロシンの経口投与用徐放性ペレット組成物，経口投与用塩酸タムスロシン製剤およびその製造方法

Legal Events

Date Code Title Description
NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08851213

Country of ref document: EP

Kind code of ref document: A2