[go: up one dir, main page]

WO2012085173A1 - Système d'administration de médicaments - Google Patents

Système d'administration de médicaments Download PDF

Info

Publication number
WO2012085173A1
WO2012085173A1 PCT/EP2011/073728 EP2011073728W WO2012085173A1 WO 2012085173 A1 WO2012085173 A1 WO 2012085173A1 EP 2011073728 W EP2011073728 W EP 2011073728W WO 2012085173 A1 WO2012085173 A1 WO 2012085173A1
Authority
WO
WIPO (PCT)
Prior art keywords
mixing device
drug delivery
delivery system
reservoir
micro
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.)
Ceased
Application number
PCT/EP2011/073728
Other languages
English (en)
Inventor
Christian Pommerau
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.)
Sanofi Aventis Deutschland GmbH
Original Assignee
Sanofi Aventis Deutschland GmbH
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 Sanofi Aventis Deutschland GmbH filed Critical Sanofi Aventis Deutschland GmbH
Publication of WO2012085173A1 publication Critical patent/WO2012085173A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/168—Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body
    • A61M5/16804—Flow controllers
    • A61M5/16827—Flow controllers controlling delivery of multiple fluids, e.g. sequencing, mixing or via separate flow-paths
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
    • B01F33/30—Micromixers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/50—Mixing receptacles
    • B01F35/52—Receptacles with two or more compartments
    • B01F35/522—Receptacles with two or more compartments comprising compartments keeping the materials to be mixed separated until the mixing is initiated
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2206/00—Characteristics of a physical parameter; associated device therefor
    • A61M2206/10—Flow characteristics
    • A61M2206/20—Flow characteristics having means for promoting or enhancing the flow, actively or passively
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/19—Syringes having more than one chamber, e.g. including a manifold coupling two parallelly aligned syringes through separate channels to a common discharge assembly

Definitions

  • the present invention relates to the field of drug delivery devices and systems and in particular to devices and systems adapted to prepare and/or to administer a medicament, preferably a multi-component medicinal fluid.
  • Numerous medicinal products are provided in liquid form and require particular preparation prior to be administered to a patient.
  • some medicinal products are provided as a multi-component product that requires mixing of its separate components prior to application. Since the various components of the medicament might be insoluble and/or may separate, e.g. due to different specific masses, a direct and immediate mixing process prior to application is generally required.
  • shelf life of the medicament and its components may increase and/or transportation and general handling of the components might become less complicated. This way, decomposition of a mixture of multiple components can be effectively prevented.
  • the flow rate of the medicinal fluid is rather low.
  • a mixing of various liquid substances is crucial and gets even more difficult as the geometry of flow through channels decreases.
  • Objects of the Invention It is therefore an object of the present invention to provide a drug delivery system for preparing and/or administering a medicinal fluid, wherein the fluid compris esnumerous liquid or soluble substances to be mixed prior to application or administering to a patient. It is a further object, to provide a liquid medicinal fluid which is highly homogeneous and which comprises a well-defined composition of various liquid substances. Furthermore, the drug delivery system should be easy to handle and should be inexpensive to manufacture. Summary of the Invention
  • the invention provides a drug delivery system for preparing and/or for administering a medicinal fluid.
  • the drug delivery system comprises at least a first reservoir filled with a first liquid substance and further comprises at least a second reservoir filled with a second liquid substance, respectively.
  • the drug delivery system further comprises a micro mixing device that has at least a first inlet port and which is in fluid-flow communication with at least the first and the second reservoir for mixing first and second substances, respectively in order to obtain the medicinal fluid to be administered.
  • the micro mixing device further has an outlet port to dispense the mixed medicinal fluid to an administering module, which, in turn is adapted to store, to administer or to apply the medicinal fluid to a patient.
  • the micro mixing device is particularly adapted to mix the at least first and second substances with each other, typically by way of emulsifying or dispersion.
  • a comparatively low flow rate can be mixed on demand, immediately prior to administering the medicinal fluid to a patient.
  • a micro mixing device By way of a micro mixing device, at least two liquid substances can be homogeneously mixed with each other, even by taking into account peculiar properties arising from the field of micro fluidics.
  • flow channels for the first and/or second liquid substance inside the micro mixing device may scale between a few micrometers up to one millimetre.
  • mixing of first and second liquid substances takes place in the micro mixing device featuring channels or ducts having diameters of less than 1 mm, preferably less than 500 pm, less than 300 pm, less than 100 pm or even less than 50 pm or less than 10 pm.
  • the drug delivery system can be adapted to various application scenarios, in particular for a variety of drug delivery devices, wherein the administering module arranged downstream the micro mixing device may be implemented as a pen-type injection system, as a syringe, as an inhaler, as a vial, as a tube or as a container for receiving and storing the mixed substances.
  • the administering module arranged downstream the micro mixing device may be implemented as a pen-type injection system, as a syringe, as an inhaler, as a vial, as a tube or as a container for receiving and storing the mixed substances.
  • the internal design and structure of the micro mixing device may individually depend on the substances to be mixed as well as on required flow rates of the medicinal fluid to be mixed therewith.
  • the micro mixing device comprises at least a first inlet port and a second inlet port that are both in fluid-flow communication with the first reservoir and the second reservoir, respectively.
  • the drug delivery system may be equipped with at least a first pump arranged between the first and/or the second reservoir and the micro mixing device for feeding the micro mixing device with the first and/or second substance, respectively.
  • a pump preferably by way of a micro pump, flow rates of first and/or second liquid substances can be individually adapted in order to prepare medicinal fluids of various composition downstream of the micro mixing device.
  • a second pump can be arranged downstream of the micro mixing device.
  • first and/or second substances might be sucked through the micro mixing device.
  • first and/or second reservoirs are coupled with respective first and/or second drive mechanisms for feeding the first and/or the second substance to the respective inlet ports of the micro mixing device.
  • first and/or second reservoirs comprise a syringe-like configuration, wherein by way of displacement of a moveable piston a certain amount of first and/or second liquid substances can be expelled from respective first and/or second reservoirs, a first and/or second pump may be effectively replaced.
  • first and/or second liquid substances can be urged through the micro mixing device.
  • the administering module comprises an injection device or wherein the administering module comprises a cartridge that is adapted to receive and to store the prepared medicinal fluid.
  • a cartridge is preferably adapted to be disposed inside a drug delivery device for dispensing a dose of the medicinal fluid e.g. by way of injection.
  • the injection device may comprise a pen-type injector or may comprise a perfusor arrangement adapted to constantly provide a medicinal fluid to a patient on the basis of a well-defined and controlled flow rate.
  • the micro mixing device is of passive type. Hence, the mixing process in the micro mixing device relies mainly on molecular diffusion and chaotic advection.
  • the micro mixing device may comprise a basic T-mixer, a Y-mixer or may implement the concept of parallel lamination and/or the concept of hydraulic focussing.
  • the micro mixing device and the mixing effect to be achieved therewith may be based on lamination, injection, chaotic advection and/or droplet generation.
  • a lamination based micro mixing device an inlet stream is divided into numerous substreams that are joined into one stream as laminae, wherein the flow in the micro mixing device is usually driven by pressure but may also be generated by electro-osmosis.
  • a serial lamination mixer geometry can be applied here. Typical serial lamination mixer principles are join- split-join; split-join; split-split-join and/or multiple intersecting micro channels.
  • serial lamination mixers an inlet stream is consecutively split and joined, typically in different directions.
  • injection mixers only a solute flow is split into many streams and is injected into a solvent flow.
  • On top of one stream is arranged an array of nozzles, which create a number of micro plumes of the solute. These plumes increase the contact surface and decrease the mixing path.
  • respective mixing channels or mixing chambers of the micro mixing device may comprise a so-called modified Tesla structure, C-shape; L-shape or a twisted micro channel shape.
  • the drug delivery system is not restricted to a single micro mixing device.
  • the system may comprise numerous micro mixing devices, that can be arranged parallel and/or serial for parallelly or sequentially mixing various
  • micro mixing devices of active type can be universally implemented here. Active micro mixing devices may for instance be based on serial or sequential segmentation, tailor dispersion, pressure disturbance, electrohydrodynamic disturbance, dielectrophoretic disturbance, electrokinetic disturbance, acoustic and/or thermal disturbance and/or on the basis of integrated microstirrer in a mixing chamber. With active micro mixing devices, at least the flow of one substance to be mixed with another one is occasionally or regularly stopped, e.g. by way of a micro pump or similar devices adapted to control a flow of a mixing substance.
  • Electrohydrodynamic disturbances can be achieved by electrodes placed along a mixing channel, wherein by changing the voltage and frequency on the electrodes has a significant influence on the mixing of the substances.
  • dielectrophoretic disturbance wherein a non-uniform electrical field is generated around the particles to be mixed, said particles may move towards and away from an electrode.
  • a temperature gradient can be generated across a number of parallel channels in order to investigate the temperature dependence of the substances to be mixed with each other.
  • the micro mixing device comprises a polymer based substrate material.
  • the micro mixing device may be manufactured on the basis of silicon and/or glass.
  • the micro mixing device may comprise steel or other metals inert to the substances to be mixed. It may for instance also comprise titanium.
  • Polymeric material can be easily prepared and manipulated, e.g. by polymeric bulk micro machining, such as hot embossing, injection moulding, casting and laser ablation.
  • the drug delivery system becomes applicable and affordable for numerous mixing applications for medical substances.
  • the invention also provides a method of preparing and/or administering a medicinal fluid, wherein the method comprises the steps of:
  • ..medicament or “medicinal product”, as used herein, means a pharmaceutical formulation containing at least one pharmaceutically active compound, wherein in one embodiment the pharmaceutically active compound has a molecular weight up to 1500 Da and/or is a peptide, a protein, a polysaccharide, a vaccine, a DNA, a RNA, a antibody, an enzyme, an antibody, a hormone or an oligonucleotide, or a mixture of the above-mentioned pharmaceutically active compound, wherein in a further embodiment the pharmaceutically active compound is useful for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, thromboembolism disorders such as deep vein or pulmonary thromboembolism, acute coronary syndrome (ACS), angina, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and/or rheumatoid arthritis, wherein in one embodiment the
  • Insulin analogues are for example Gly(A21 ), Arg(B31 ), Arg(B32) human insulin; Lys(B3), Glu(B29) human insulin; Lys(B28), Pro(B29) human insulin; Asp(B28) human insulin; human insulin, wherein proline in position B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein in position B29 Lys may be replaced by Pro; Ala(B26) human insulin; Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) human insulin.
  • Insulin derivates are for example B29-N-myristoyl-des(B30) human insulin; B29-N- palmitoyl-des(B30) human insulin; B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29 human insulin; B28-N-palmitoyl- LysB28ProB29 human insulin; B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N- palmitoyl- ThrB29LysB30 human insulin; B29-N-(N-palmitoyl-Y-glutamyl)-des(B30) human insulin; B29-N-(N-lithocholyl-Y-glutamyl)-des(B30) human insulin; ⁇ 29- ⁇ -( ⁇ - carboxyheptadecanoyl)-des(B30) human insulin and B29-N-( -carboxy
  • Exendin-4 for example means Exendin-4(1 -39), a peptide of the sequence H-His-Gly-
  • Exendin-4 derivatives are for example selected from the following list of compounds:
  • H-(Lys)6-des Pro36, Pro37, Pro38 [Met(0)14, Asp28] Exendin-4(1 -39)-(Lys)6-NH2, H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(0)14, Asp28] Exendin-4(1 -39)-(Lys)6-NH2, H-Lys6-des Pro36 [Met(0)14, Trp(02)25, Asp28] Exendin-4(1 -39)-Lys6-NH2,
  • Hormones are for example hypophysis hormones or hypothalamus hormones or regulatory active peptides and their antagonists as listed in Rote Liste, ed. 2008, Chapter 50, such as Gonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin, Buserelin, Nafarelin, Goserelin.
  • Gonadotropine Follitropin, Lutropin, Choriongonadotropin, Menotropin
  • Somatropine Somatropin
  • Desmopressin Terlipressin
  • Gonadorelin Triptorelin
  • Leuprorelin Buserelin
  • Nafarelin Goserelin.
  • a polysaccharide is for example a glucosaminoglycane, a hyaluronic acid, a heparin, a low molecular weight heparin or an ultra low molecular weight heparin or a derivative thereof, or a sulphated, e.g. a poly-sulphated form of the above-mentioned polysaccharides, and/or a pharmaceutically acceptable salt thereof.
  • An example of a pharmaceutically acceptable salt of a poly-sulphated low molecular weight heparin is enoxaparin sodium.
  • Pharmaceutically acceptable salts are for example acid addition salts and basic salts. Acid addition salts are e.g. HCI or HBr salts.
  • Basic salts are e.g. salts having a cation selected from alkali or alkaline, e.g. Na+, or K+, or Ca2+, or an ammonium ion N+(R1 )(R2)(R3)(R4), wherein R1 to R4 independently of each other mean: hydrogen, an optionally substituted C1 -C6-alkyl group, an optionally substituted C2-C6-alkenyl group, an optionally substituted C6-C10-aryl group, or an optionally substituted C6-C10- heteroaryl group.
  • R1 to R4 independently of each other mean: hydrogen, an optionally substituted C1 -C6-alkyl group, an optionally substituted C2-C6-alkenyl group, an optionally substituted C6-C10-aryl group, or an optionally substituted C6-C10- heteroaryl group.
  • R1 to R4 independently of each other mean: hydrogen, an optionally substituted C1 -C
  • solvates are for example hydrates.
  • Figure 1 schematically illustrates a drug delivery system according to a first embodiment
  • Figure 2 shows a drug delivery system according to a second embodiment
  • Figure 3 is illustrative of a third embodiment, wherein a pump is arranged
  • FIG. 1 shows a drug delivery system 1 0 comprising a first reservoir 12 filled with a first liquid substance and further comprising a second reservoir 14 filled with a second liquid substance. Both substances are to be fed through respective channels or ducts 16, 1 8 to a micro m ixing device 20.
  • a pump 22 is arranged downstream the first and second reservoirs 12, 14 but upstream the m icro m ixing device 20.
  • the at least first and second substances can be mutually m ixed and may be dispensed in form of a homogeneous emulsion or dispersion to an adm inistering module 32.
  • the m icro m ixing device 20 the at least two substances are emulsified and/or dispersed in order to produce a homogeneous medicinal product to be fed through the outlet port 30 to the adm inistering module 32.
  • the adm inistering module 32 may comprise a cartridge for a drug delivery device, such as a pen-type injector or a perfusor.
  • the cartridge may be adapted to be inserted into a respective drug delivery device when disconnected from the outlet port 30.
  • first and/or second reservoirs 12, 14 may be disconnected or reconnected from or with the respective ducts 16, 1 8, for instance in order to replace an empty reservoir 12, 14 by a filled one.
  • the first and/or the second duct 16, 1 8 are provided with a separate pump 22, 24.
  • the m icro m ixing device 20 comprises two separate inlet ports 26, 28, each of which being separately connected to the first and the second pump 22, 24, respectively.
  • a composition of the medicinal product to be m ixed by the m icro m ixing device 20 can be arbitrarily modified, e.g. by changing the flow rates of first and/or second pumps 22, 24, respectively.
  • first and/or second reservoirs 12, 14 can be equipped with first and/or second drive mechanisms 36, 38 that allow to expel or to urge the respective liquid substance contained in said reservoirs 12 , 14 into the ducts or flow channels 16, 1 8.
  • a single pump 34 is arranged downstream of the micro mixing device 20. This way, first and/or second substances can be sucked through the channel system 16, 18 into and through the micro mixing device 20.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Anesthesiology (AREA)
  • Vascular Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Infusion, Injection, And Reservoir Apparatuses (AREA)

Abstract

La présente invention concerne un système d'administration de médicaments pour préparer et/ou administrer un fluide médicinal, comprenant : - au moins un premier réservoir (12) rempli d'une première substance liquide, - au moins un second réservoir (14) rempli d'une seconde substance liquide, - un dispositif de micro-mélange (20) ayant au moins un premier orifice d'entrée (24, 26) qui est en communication d'écoulement de fluide avec au moins le premier et le second réservoir (12, 14) pour mélanger les première et seconde substances et pour obtenir le fluide médicinal et pour distribuer le fluide médicinal par l'intermédiaire d'un orifice de sortie (30) à un module d'administration (32).
PCT/EP2011/073728 2010-12-23 2011-12-22 Système d'administration de médicaments Ceased WO2012085173A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP10196818.8 2010-12-23
EP10196818 2010-12-23

Publications (1)

Publication Number Publication Date
WO2012085173A1 true WO2012085173A1 (fr) 2012-06-28

Family

ID=44246340

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2011/073728 Ceased WO2012085173A1 (fr) 2010-12-23 2011-12-22 Système d'administration de médicaments

Country Status (1)

Country Link
WO (1) WO2012085173A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016067179A1 (fr) 2014-10-29 2016-05-06 Wockhardt Limited Dispositif d'administration de médicament pour l'administration de deux doses multiples ou plus de médicaments, indépendamment sélectionnables par l'utilisateur avec des mécanismes de verrouillage de dose variable actionnable par l'utilisateur

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050272144A1 (en) * 2004-06-08 2005-12-08 Konica Minolta Medical & Graphic, Inc. Micro-reactor for improving efficiency of liquid mixing and reaction
US20070047388A1 (en) * 2005-08-25 2007-03-01 Rockwell Scientific Licensing, Llc Fluidic mixing structure, method for fabricating same, and mixing method

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050272144A1 (en) * 2004-06-08 2005-12-08 Konica Minolta Medical & Graphic, Inc. Micro-reactor for improving efficiency of liquid mixing and reaction
US20070047388A1 (en) * 2005-08-25 2007-03-01 Rockwell Scientific Licensing, Llc Fluidic mixing structure, method for fabricating same, and mixing method

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences", 1985, MARK PUBLISHING COMPANY
"Rote Liste", 2008

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016067179A1 (fr) 2014-10-29 2016-05-06 Wockhardt Limited Dispositif d'administration de médicament pour l'administration de deux doses multiples ou plus de médicaments, indépendamment sélectionnables par l'utilisateur avec des mécanismes de verrouillage de dose variable actionnable par l'utilisateur

Similar Documents

Publication Publication Date Title
EP2482872B1 (fr) Procédé pour l'assemblage d'un dispositif d'administration de médicaments, assemblage pour un dispositif d'administration de médicaments et tige de piston pour un dispositif d'administration de médicaments
US9242051B2 (en) Needle assembly for drug delivery devices
US9592341B2 (en) Arrangement for use in a drug delivery device
US20150013827A1 (en) Reservoir or medicated module for a drug delivery system and method of and assembly for filling the same
SG181790A1 (en) Piston for a cartridge and piston rod for a drug delivery device
US20130211370A1 (en) Medicine Delivery Device
US10137240B2 (en) Capillary channel structure for dispense interface
WO2012085173A1 (fr) Système d'administration de médicaments
US8864722B2 (en) Cartridge holder and drug delivery device
EP2442852B1 (fr) Agencement d'injection pour médicament fluide
EP2453952B1 (fr) Conteneur de médicaments
EP2477680B1 (fr) Unité de verrouillage et de contrôle à intégrer dans un appareil médical
EP2462346B1 (fr) Agencement d'injection
US9220839B2 (en) Assembly for use in a drug delivery device
DK2470240T3 (en) Arrangement for delivery of a liquid medication

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11807917

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11807917

Country of ref document: EP

Kind code of ref document: A1