EP2094736A1 - Acide hyaluronique réticulé et son procédé de préparation - Google Patents

Acide hyaluronique réticulé et son procédé de préparation

Info

Publication number
EP2094736A1
EP2094736A1 EP07866489A EP07866489A EP2094736A1 EP 2094736 A1 EP2094736 A1 EP 2094736A1 EP 07866489 A EP07866489 A EP 07866489A EP 07866489 A EP07866489 A EP 07866489A EP 2094736 A1 EP2094736 A1 EP 2094736A1
Authority
EP
European Patent Office
Prior art keywords
hyaluronic acid
acid according
crosslinked
coupling agent
reaction
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Withdrawn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
EP07866489A
Other languages
German (de)
English (en)
French (fr)
Inventor
Jérôme ASIUS
Nicolas Riviere
Bénédicte ASIUS
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.)
Sinclair Pharmaceuticals Ltd
Original Assignee
Stiefel Research Australia Pty Ltd
Stiefel Laboratories Inc
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 Stiefel Research Australia Pty Ltd, Stiefel Laboratories Inc filed Critical Stiefel Research Australia Pty Ltd
Publication of EP2094736A1 publication Critical patent/EP2094736A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/145—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/042—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
    • C08B37/0027—2-Acetamido-2-deoxy-beta-glucans; Derivatives thereof
    • C08B37/003—Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
    • C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates

Definitions

  • the present invention relates to a novel crosslinked hyaluronic acid and its method of preparation and uses, especially cosmetics.
  • Hyaluronic acid is a polysaccharide consisting of D-glucuronic acid units and N-acetyl-D-glucosamine units, which is particularly known for use in reconstructive or ocular surgery or in the aesthetic field as a filling product for wrinkles.
  • hyaluronic acid is preferred over other fillers because of its biocompatibility and physicochemical properties.
  • it has the disadvantage of degrading quickly, thus requiring repeated injections.
  • various methods of crosslinking hyaluronic acid to make it less sensitive to various degradation factors such as enzymatic and / or bacterial attacks, temperature and free radicals and to improve its resistance to degradation in vivo and therefore its duration of action. These processes involve, in particular, etherification, esterification or amidification of the hydroxyl and / or acid functions of the native hyaluronic acid.
  • EP-I 535 952 discloses a coating consisting of crosslinked hyaluronic acid formed in situ by reaction of a polylysine with hyaluronic acid in the presence of EDC and NHS at a pH of 2 to 9 and preferably from 4 to 7.5.
  • the article provided with this coating may in particular be a prosthesis that can be used in cosmetic surgery.
  • This document does not disclose crosslinked hyaluronic acid precipitated in an organic solvent in order to be available in dry form and susceptible thus to be formulated as a hydrogel extemporaneously.
  • US Pat. No. 6,632,457 discloses a modified hyaluronic acid prepared by reacting a primary amine with a carbodiimide-activated hyaluronic acid such as EDC and an N-hydroxysulfosuccinimide derivative such as NHS. at a pH of 7.0 to 8.5.
  • the compound obtained can be cross-linked under physiological conditions, for example with glutaraldehyde, to obtain a hydrogel which remains sensitive to glycosidases and degrades substantially completely in less than 50 hours. This kinetics of degradation is compatible with the intended use as a vector of cells and growth factors but is not suitable for use as a filler in cosmetic surgery, for example.
  • the application WO 2006/021644 describes a process for preparing cross-linked hyaluronic acid by activating hyaluronic acid with a coupling agent such as EDC and a catalyst such as NHS, followed by a reaction with a polypeptide such as dilysine, at a pH of 4 to 10, for example from 4 to 6.
  • the pH may optionally be raised, at the end of the reaction, to a value of 6 to 7 to increase the extraction yield during the reaction. precipitation phase.
  • the crosslinking is carried out in an acidic medium which is then optionally neutralized, or it is carried out in basic medium without subsequent modification of pH.
  • the Applicant has discovered that the use of a The acidic pH during the reaction phase was not always favorable to the amidification reaction and could lead, as indicated previously, to parasitic reactions, in particular of intramolecular esterification, which may affect the physicochemical properties of the product obtained. .
  • the Applicant has discovered quite fortuitously that the pH of precipitation in an organic solvent of hyaluronic acid crosslinked with a polypeptide determined its rheological properties and its sensitivity to degradation factors such as temperature, the free radicals and enzymes such as hyaluronidases. Following multiple experiments, the Applicant then identified the optimal precipitation conditions for obtaining a crosslinked hyaluronic acid insensitive to thermal degradation, that is to say, retaining its properties. rheological properties after redissolution of the precipitated compound and sterilization. Everything happens as if reticulated hyaluronic acid once reformulated a "memory" of its molecular organization at the time of precipitation. It has furthermore been demonstrated that this molecular arrangement furthermore influences the ability of the polymer to resolubilize.
  • the aforementioned method makes it possible to densify and solidify the macromolecular network of hyaluronic acid not only by means of covalent bonds with the crosslinking agent, but also by means of ionic interactions and / or or hydrogen bonds developing at the moment of precipitation.
  • the present invention therefore relates to a crosslinked hyaluronic acid, obtainable by a process comprising:
  • the crosslinked hyaluronic acid obtained according to the invention is soluble in water.
  • this expression it is meant that 1 g of the dehydrated fibers obtained as described above are disintegrated in a few minutes and solubilize completely in one liter of saline solution after a few hours, without stirring.
  • the hyaluronic acid used in the above process is generally used in the native state, that is to say as naturally occurring in a living organism or excreted by the bacteria during its production by bacterial fermentation. It thus generally has a molecular weight ranging from 500,000 to 7,000,000 Daltons and is usually used in the form of sodium salt.
  • Hyaluronic acid is activated before crosslinking, using a coupling agent and a coupling aid.
  • Examples of coupling agents are water-soluble carbodiimides such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC), 1-ethyl-3- (3-trimethylaminopropyl) carbodiimide (ETC) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC).
  • EDC water-soluble carbodiimides
  • ETC 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
  • ETC 1-ethyl-3- (3-trimethylaminopropyl) carbodiimide
  • EDC 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
  • CMC cyclohexyl-3- (2-morphilinoethyl) carbodiimide
  • coupling aids are N- hydroxy succinimide (NHS), N-hydroxy benzotriazole (HOBt), 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazole (HOOBt), 1-hydroxy-7-azabenzotriazole
  • the molar ratio of the coupling agent to the carboxylic acid units of hyaluronic acid be between 2% and 200%, more preferably between 5% and 100%.
  • the molar ratio of the coupling aid to the coupling agent is advantageously between 1: 1 and 3: 1, preferably between 1.5: 1 and 2.5: 1 inclusive, and more preferentially equal to 2.
  • the activation reaction of the hyaluronic acid by the coupling agent can be carried out at a pH ranging for example from 3 to 6, preferably from 4 to 5.
  • the concentration of hyaluronic acid in the reaction medium is for example between 0.1 and 5% by weight, for example between 0.1 and 1% by weight, inclusive.
  • the crosslinking agent comprises at least 50% by weight, and is advantageously constituted of an oligo- or polypeptide which can be a homo- or copolypeptide statistic, block, segmented, grafted or star.
  • the crosslinking agent is generally in salt form and in particular hydrochloride or optionally hydrobromide or trifluoroacetate, in particular.
  • the number of amine functions of the polypeptide involved represents from (1 to 100%), preferably from 10 to 50%, of the number of carboxylic acid functions of the hyaluronic acid involved.
  • the coupling agent is used in stoichiometric amount relative to the amine functions of the crosslinking agent.
  • the amount of carboxylic acid functions of hyaluronic acid that are activated is equal to the amount of amine functions that will be added to the second step.
  • the agent of coupling is carried out in stoichiometric amount with respect to the carboxylic acid functions of hyaluronic acid.
  • the quantity of crosslinking agent used in the second step may, for example, be less than 30%, better still, less than 10%, or even about 5% (in number of moles of crosslinking agent relative to the number of moles of carboxylic acid functions).
  • the crosslinking reaction is generally carried out under temperature conditions and for a time entirely conventional for those skilled in the art, for example at a temperature of 0-45 0 C, preferably 5- 25 ° C for 1 to 1Oh, preferably 1 to 6h.
  • the pH of the reaction is between 8 and 12 and preferably between 8 and 10 (limits included). This pH can be adjusted using any base, preferably a weakly nucleophilic base such as an amine such as diisopropylethylamine (DIEA).
  • DIEA diisopropylethylamine
  • This reaction is usually carried out in a solvent such as an aqueous solution of sodium chloride.
  • the concentration of hyaluronic acid in the reaction medium is, for example, between 0.01 and 5% by weight, for example between 0.1 and 1% by weight, limits included.
  • the pH of the reaction medium is adjusted to a value ranging from 5 to 7 and preferably from 5.5 to 7 with the aid of any acid such as hydrochloric acid, before the crosslinked hyaluronic acid obtained is precipitated.
  • the precipitation step is carried out in an organic solvent such as ethanol, isopropanol, ether or acetone, or mixtures thereof, for example, ethanol being preferred in this invention.
  • the solvent is advantageously used in an amount representing from 5 to 20 times, for example approximately 10 times, the volume of reaction medium.
  • a possible drying step is then preferably carried out, so as to obtain a dehydrated form of crosslinked hyaluronic acid which is easier to handle and is better preserved.
  • the preservation can in particular be carried out in negative cold.
  • the invention also relates to the process for producing a crosslinked hyaluronic acid, as described above.
  • This process may also comprise other steps than those explicitly mentioned and in particular a step of mixing said dehydrated crosslinked hyaluronic acid with an aqueous solvent, such as a sodium chloride solution, a physiological saline solution or an injectable buffered solution (especially a saline solution of phosphate buffer), to form a hydrogel.
  • an aqueous solvent such as a sodium chloride solution, a physiological saline solution or an injectable buffered solution (especially a saline solution of phosphate buffer)
  • concentration of hyaluronic acid in said hydrogel may range from 1 to 4% and preferably from 1.5 to 3% w / v.
  • the invention therefore also relates to such a hydrogel, containing a crosslinked hyaluronic acid as described above, in an aqueous solvent.
  • the measurement of the elastic modulus, the viscous modulus and the loss angle can be carried out in the following manner: the hydrogel is treated with a 4cm, 4 ° cone-plane geometry at a temperature of 25 ° C. It undergoes a non-destructive viscoelastic test at IHz, with an imposed deformation of 1%.
  • the measurement of the elastic modulus is carried out using a rheometer type AR 1000 from TA Instruments. The same apparatus can be used to measure the viscosity using a shear rate of 50 ° ⁇ 2 sec ⁇ x .
  • the invention therefore also relates to a sterilized hydrogel containing hyaluronic acid crosslinked by a crosslinking agent containing at least 50% by weight of oligo- or polypeptide, characterized in that it has a variation of its elastic modulus of less than 30% after stoving at 93 ° C for 1 hour.
  • This hydrogel is advantageously used for the manufacture of implants.
  • These implants can in particular be injected subcutaneously (hypodermic) or intradermally into the fibrous tissue.
  • a carrier fluid comprising at least one polysaccharide, for example at least one cellulose derivative such as carboxymethylcellulose and / or at least one glycosaminoglycan such as sodium hyaluronate and / or particles of a biocompatible bioresorbable material such as polylactic acid (PLLA), polyglycolic acid (PGA), poly (lactic-co-glycolic acid) (PLGA), tricalcium phosphate (TCP), hydroxyapatite (PAHs), and mixtures thereof.
  • PLLA polylactic acid
  • PGA polyglycolic acid
  • PLGA poly (lactic-co-glycolic acid)
  • TCP tricalcium phosphate
  • PAHs hydroxyapatite
  • the implants according to the invention are bioabsorbable, in that they are capable of degrading in the body in 6 to 18 months.
  • hyaluronic acid-deficient cavity or organ typically in dermatology, aesthetic medicine or in orthopedic treatments
  • reconstitution of an effused volume during surgical procedures typically in ocular surgery
  • the aforementioned implant is particularly well suited for use in filling facial wrinkles and fine lines and / or scars of the human body.
  • the present invention therefore also relates to the use of crosslinked hyaluronic acid as described above for the manufacture of injectable implants intended for use in cosmetic and / or restorative surgery, for the manufacture of fillers, especially wrinkles, fine lines, scars or skin depressions such as lipodystrophies.
  • the crosslinking reaction (scheme 1) consists of a double peptide coupling between the carboxylic acid functions of two hyaluronic acid chains and the amine functions of dilysine.
  • the coupling reagents used are 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS).
  • the first step consists of a nucleophilic attack of the carboxylic acid function of hyaluronic acid on the carbodiimide function of the coupling agent EDC.
  • the resulting O-acylurea is then substituted with NHS to form a more stable activated ester (production of 1-ethyl-3- (3-dimethylaminopropyl) urea).
  • O-acylurea can rearrange into inert N-acylurea in a slightly acidic aqueous medium and during a long reaction time.
  • the last step consists finally in the nucleophilic attack of one of the amine functions of the dilysine (preferably terminal, sterically favored) on the activated ester in order to form an amide bond with NHS release.
  • a 500 ml glass reactor 3 g of sodium chloride are successively introduced into 300 ml of milliQ water. After dissolving the sodium chloride with the sonicator, 2 g of hyaluronic acid (HTL Sari, batch) are introduced into the reactor containing the saline solution.
  • HTL Sari hyaluronic acid
  • reaction mixture is removed from the refrigerator and stirred at room temperature (18-25 ° C) for 10 minutes, (visually the solution should be perfectly clear and homogeneous having a certain viscosity, such as fluid honey).
  • the stirring used is of mechanical type with a stirrer in the form of a half-moon teflon.
  • the rotation speed is 60 rpm.
  • a solution of 464 mg (4.03 mmol) of N-hydroxysuccinimide (ACROS, purity 98%, hereinafter NHS) is then prepared in 5 ml of milliQ water in a hemolysis tube and then vortexed to dissolve the totality of the NHS. This solution is added to the reaction medium dropwise at 5 ml / mm.
  • ACROS N-hydroxysuccinimide
  • the mixture is left stirring for thirty minutes and then the aqueous solution of dilysme is added to the reaction medium at the rate of 1 ml / mm.
  • This solution is prepared by vortex solubilizing in 1 ml of water rruiliQ, 233 mg (0.67 mmol) of dilysme hydrochloride (BACHEM supplier, ref G2675), then 1302 ⁇ l f 10, 08 mmol) of propylethylamine (supplier ACROS ref 115225000, hereinafter DIEA), all in a hemolysis tube.
  • This mixture has two distinct phases forming a reversible emulsion after vigorous stirring. It is attempted to mix the emulsion as much as possible while it is added to the reaction medium.
  • the pH of the reaction medium must be between 8.5 and 10.5.
  • the pH of the solution is adjusted before precipitation with 1M HCl to reduce it to a pH of 5.7.
  • a reactor of a liter capacity, equipped with a mechanical stirrer and a stirring rod in the form of a rake is prepared.
  • 420 ml of ethanol at 95 ° are poured into this reactor and the mechanical stirring is started at a very high speed (approximately 1000 rpm).
  • reaction mixture containing the crosslinked hyaluronate is then aspirated with a 50 ml syringe and then fed continuously into the reactor.
  • the solution should be clear, colorless and fairly viscous.
  • the product After removing the syringe from the refrigerator, the product is rapidly stirred with mechanical agitation at a speed of 1000 rpm.
  • the stirring rod used is a laboratory spatula shaped like a stainless steel spoon.
  • the stirring time is about 5 minutes for this product, but varies according to the viscosity.
  • the final gel must be colorless and perfectly homogeneous.
  • Tested products All tested products are sterile products.
  • Table 1 summarizes the results obtained for the various tested reticulated hyaluronic acids.
  • modified hyaluronic acids according to the invention exhibit a lower drop in their elastic modulus than the commercially available crosslinked hyaluronic acids, which shows that they are more resistant to degradation factors.
  • Classes from 1 to 5 were used, which represent a synthetic note taking into account the elasticity and the viscosity of the gel. The more the gel is considered elastic, the higher the score. On the other hand, a non-homogeneous and / or fluid gel has a low score.
  • cross-linked hyaluronic acids precipitated at a pH that is too acidic give hydrogels having good viscoelasticity (provided that they can be reformulated, which is not always possible), but which deteriorate markedly during the transition to and will be sensitive to endogenous degradation factors.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Vascular Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Surgery (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Materials Engineering (AREA)
  • Molecular Biology (AREA)
  • Polymers & Plastics (AREA)
  • Biochemistry (AREA)
  • Dermatology (AREA)
  • Dispersion Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Materials For Medical Uses (AREA)
  • Medicinal Preparation (AREA)
EP07866489A 2006-11-10 2007-10-25 Acide hyaluronique réticulé et son procédé de préparation Withdrawn EP2094736A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0609866A FR2908415B1 (fr) 2006-11-10 2006-11-10 Acide hyaluronique reticule et son procede de preparation
PCT/FR2007/052245 WO2008056069A1 (fr) 2006-11-10 2007-10-25 Acide hyaluronique réticulé et son procédé de préparation

Publications (1)

Publication Number Publication Date
EP2094736A1 true EP2094736A1 (fr) 2009-09-02

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Application Number Title Priority Date Filing Date
EP07866489A Withdrawn EP2094736A1 (fr) 2006-11-10 2007-10-25 Acide hyaluronique réticulé et son procédé de préparation

Country Status (12)

Country Link
US (1) US20090263447A1 (ru)
EP (1) EP2094736A1 (ru)
JP (1) JP5389661B2 (ru)
KR (1) KR101478849B1 (ru)
CN (1) CN101611063B (ru)
AU (1) AU2007316520B2 (ru)
BR (1) BRPI0718577A2 (ru)
CA (1) CA2668650C (ru)
FR (1) FR2908415B1 (ru)
MX (1) MX2009004969A (ru)
RU (1) RU2456299C2 (ru)
WO (1) WO2008056069A1 (ru)

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WO2008056069A1 (fr) 2008-05-15
US20090263447A1 (en) 2009-10-22
CA2668650C (en) 2015-05-26
MX2009004969A (es) 2009-05-21
KR101478849B1 (ko) 2015-01-02
AU2007316520A1 (en) 2008-05-15
FR2908415A1 (fr) 2008-05-16
FR2908415B1 (fr) 2009-01-23
RU2456299C2 (ru) 2012-07-20
JP2010509425A (ja) 2010-03-25
BRPI0718577A2 (pt) 2014-03-11
AU2007316520B2 (en) 2011-09-29
CN101611063A (zh) 2009-12-23
RU2009120214A (ru) 2010-12-20
CN101611063B (zh) 2013-02-20

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