EP2170961A1 - Dispersion d'acide hyaluronique, sa préparation et son application - Google Patents

Dispersion d'acide hyaluronique, sa préparation et son application

Info

Publication number
EP2170961A1
EP2170961A1 EP07786333A EP07786333A EP2170961A1 EP 2170961 A1 EP2170961 A1 EP 2170961A1 EP 07786333 A EP07786333 A EP 07786333A EP 07786333 A EP07786333 A EP 07786333A EP 2170961 A1 EP2170961 A1 EP 2170961A1
Authority
EP
European Patent Office
Prior art keywords
hyaluronic acid
acid dispersion
dispersion according
cross
linked
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Withdrawn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
EP07786333A
Other languages
German (de)
English (en)
Inventor
Christine Kreiner
Lidia Nachbaur
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.)
S & V Technologies AG
Original Assignee
S & V Technologies 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 S & V Technologies AG filed Critical S & V Technologies AG
Publication of EP2170961A1 publication Critical patent/EP2170961A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • 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
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/48—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with macromolecular fillers
    • 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
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • 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
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
    • 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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/24—Materials or treatment for tissue regeneration for joint reconstruction
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L2205/00—Polymer mixtures characterised by other features
    • C08L2205/02—Polymer mixtures characterised by other features containing two or more polymers of the same C08L -group
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L2205/00—Polymer mixtures characterised by other features
    • C08L2205/22—Mixtures comprising a continuous polymer matrix in which are dispersed crosslinked particles of another polymer

Definitions

  • Hyaluronic acid dispersion preparation and application
  • Hyaluronic acid and preparations thereof have long been known.
  • Hyaluronic acid is an important component of human tissue and occurs in the human body in the eye (vitreous), in the joints of the bones and in the epidermis. In the body of a 70 kg person approx. 15 g of hyaluronic acid are present.
  • Hyaluronic acid is a macromolecular chain of disaccharides that consists of two glucose derivatives: D-glucuronic acid and N-acetyl-D-gucosamine.
  • the glucuronic acid is linked to the N-acetylglucosamine, which in turn is linked to the next glucuronic acid in the polymeric chain / (1 ⁇ 4).
  • a chain typically consists of 250-50,000 disaccharides.
  • Hyaluronic acid and its preparations are used in the cosmetic, pharmaceutical and medical sectors.
  • hyaluronic acid preparations are used for the treatment of joint complaints, in particular arthritic complaints.
  • the Hyalu serves Medicine hyaluronic acid preparations are used for the treatment of joint complaints, in particular arthritic complaints.
  • hyaluronic acid injected directly into the joint, serves as synovial fluid to improve the mobility of the joint apparatus.
  • Another application of hyaluronic acid preparations in medicine is the field of ophthalmology, in particular cataract surgery.
  • hayluronic acid preparations serve as a medicament carrier system, because hyaluronic acid, due to its high molecular weight and its special chemical structure, is able to stabilize and quasi encapsulate chemical substances in order to transport them into the cell interior with the aid of a suitable, acceptable carrier material where the chemical substances unfold their effect.
  • hyaluronic acid is used in particular as a water reservoir.
  • Hyaluronic Acid By injecting Hyaluronic Acid directly under the skin, water deposits are formed that swell up like a sponge, visibly “wrinkling” wrinkles outward, and when injected into the lips, make them appear plump and well-formed.
  • hyaluronic acid increases water retention the skin retains a fresh, youthful and toned appearance while remaining elastic and supple, and with repeated use, it also reduces the appearance of minor wrinkles on topically applied hyaluronic acid preparations.
  • hyaluronic acid when used topically, is usually used in solution or emulsified.
  • preparations based on yellow or emulsion are often not suitable because the other ingredients, such as preservatives, emulsifiers, solubilizers and surfactants, but also pigments and dyes, the degradation reactions of hyaluronic acid, so the cleavage of the molecular chains strongly catalyze.
  • Hyaluronic acid preparations are therefore often only of insufficient durability, usually with little effect.
  • An improvement in terms of reduced chemical degradation of the molecules is provided by hyaluronic acid preparations having hyaluronic acid chains with cross-linked structures.
  • the reactive side groups are reacted with suitable reactants, ie bridge molecules, whereby a three-dimensional network structure is formed. This, in turn, results in a large-scale network structure with excellent water storage capacity.
  • Hyaluronic acid is, as already stated, a macromolecule, which has a high space requirement due to its high molecular weight and its three-dimensional, coiled structure. The use concentrations are therefore rather low.
  • the creased, band-like entangled structure is due to the fact that the individual molecule sections enter into constructive interactions with each other, and thereby also solvent molecules, usually water, attach.
  • Due to its chemical and physical structure, hyaluronic acid is a viscoelastic gel solution in water. The viscosity is still significantly increased by cross-linking.
  • crosslinked hyaluronic acid molecules are substantially more stable to hydroxylation and / or chemical and enzymatic degradation by reactive molecules than non-crosslinked hyaluronic acid chains. Therefore, especially in medicine, aesthetics and cosmetics, where a lasting effect is crucial to the success of the treatment, exclusively stabilized cross-linked hyaluronic acid is used.
  • cross-linked hyaluronic acid Due to the high viscosity of cross-linked hyaluronic acid, the applicability by injection to wrinkle injection is limited, but limited.
  • the crosslinked hyaluronic acid is diluted in the dispersion to be applied, in order to be able to use relatively thin needles of inner diameter.
  • the object of the present invention is to provide a hyaluronic acid preparation which is easy to inject and disperse and which is resistant to hydroxylation. - A -
  • composition as disclosed in claim 1 Surprisingly, it has been found that a hyaluronic acid dispersion with a dispersed phase consisting of particles of crosslinked hyaluronic acid in a continuous phase of non-crosslinked hyaluronic acid achieves the stated object.
  • hyaluronic acid is a macromolecule.
  • cross-linked hyaluronic acid is no longer able to dissolve in a surrounding solvent because of its high molecular weight and its coiled structure. Therefore, one speaks of a Hyaluronklaredispersion, so a distribution of hyaluronic acid in the surrounding solvent.
  • the predominant proportion of "solvent" or rather dispersant, the continuous phase consists of uncrosslinked hyaluronic acid.
  • the behavior of the Hyaluronic acid dispersion is viscoelastic, in particular thixotropic, which means that the dispersion liquefies upon application of shear force and re-solidifies immediately upon completion of the shear force and returns substantially to its original viscous structure.
  • the solvent water is a highly polar molecule of oxygen and hydrogen atoms.
  • the hyaluronic acid also has polar groups in its chemical structure. In cross-linked structure, however, the polar anchor groups are reacted with another molecule, so that the polar character is reduced. This results in a significantly reduced solubility of the crosslinked in aqueous solution Hyaluronic acid. Like a drop of oil in an aqueous environment, the cross-linked hyaluronic acid in water therefore increasingly coalesces to form insoluble subregions in which the viscosity is extremely high. Due to the low solubility and therefore the pronounced formation of balls, such a preparation has a high viscosity and thus a lower dispersibility and injectability.
  • the effect of shearing force causes the viscosity of the dispersion according to the invention to decrease markedly at the moment of the force effect, and to build up again when the shear force is reduced.
  • This thixotropy of the hyaluronic acid dispersion according to the invention is decisive for the ease of injectability, which makes it possible to use smaller needle diameters when injected.
  • the hyaluronic acid dispersion according to the invention is optimally suitable for gentle tissue augmentation Once injected under the skin, the viscosity builds up again, so that in particular the wrinkle filling effect occurs immediately after injection and thus the hyaluronic acid dispersion according to the invention for viscoaugmentation long-term effectiveness and at the same time excellent biocompatibility is suitable.
  • the proportion of cross-linked hyaluronic acid is approximately between 0.1 and 99.0 wt .-%, based on the total weight of Hyaluronklaredispersion. Preferably, 50 to 95 wt .-% are used. Higher concentrations than 99% by weight lead to an increase in viscosity, ie to a viscosity that does not differ significantly from pure cross-linked hyaluronic acid. Such a dispersion can likewise be injected if the particle size is selected accordingly. In order to bring sufficiently cross-linked hyaluronic acid to the site of action, about 50 to 95% by weight of cross-linked hyaluronic acid are optimally suited to achieving a long-term effect. At lower levels, the duration of effectiveness may be shortened.
  • the hyaluronic acid particles or dispersion droplets of the crosslinked hyaluronic acid preferably have a diameter of about 80 to 300 ⁇ m.
  • the particle diameter is preferably 80 to 300 microns.
  • the lower limit of the particle diameter is to be selected in view of the desired high efficiency and the desired thixotropic properties.
  • a crosslinked hyaluronic acid having a molecular weight of about 0.8 to 3 million daltons is used.
  • Low molecular weight hyaluronic acid molecules and therefore less cross-linked hyaluronic acid molecules are therefore subject to accelerated degradation and thus can not develop a long-term effect.
  • Hyaluronklaredispersion according to the invention is shown schematically.
  • Cross-linked hyaluronic acid particles 1 are distributed in entangled linear hyaluronic acid 2.
  • the entangled linear hyaluronic acid 2 also provides shell-in-shell protection against degradation, thereby providing the desired sustained efficacy after injection.
  • the rheological measurements were carried out on the shear stress controlled rheometer AR-G2 (Ta Instruments) at 25 ° C.
  • Table 1 shows an overview of the measurement conditions: Table 1: Overview of the measurement conditions
  • Figure 1 Dependence of the complex oscillation viscosity ⁇ * , the storage modulus G 'and the loss modulus G "on the applied angular frequency ⁇ for Example 1 (8 mg / ml cross-linked and 0.4 mg / ml non-crosslinked sodium hyaluronate solution).
  • Figure 2 Dependence of the complex vibration viscosity ⁇ *, the storage modulus G 'and the loss modulus G "on the applied angular frequency ⁇ for Example 2 (22 mg / ml cross-linked and 2 mg / ml uncrosslinked sodium hyaluronate solution).
  • Figure 3 Dependence of the complex oscillation viscosity ⁇ *, the storage modulus G 'and the loss modulus G "on the applied angular frequency ⁇ for example 3 (22 mg / ml crosslinked and 2 mg / ml uncrosslinked sodium hyaluronate solution).
  • the oscillator experiments of the samples of the three exemplary embodiments each have a plateau behavior of the modules over the entire measuring range.
  • the behavior of the examples is viscoelastic due to a quasipermanent network.
  • Storage and loss module of Example 1 are about a decade below the two examples 2 and 3.
  • the development of the complex viscosity ⁇ ⁇ * ⁇ in Example 1 has a similar course to both Examples 2 and 3.
  • the values of the In this case, game 1 is about a decade lower than the other two examples.
  • the reason for this is the low concentration of hyaluronic acid particles, the height of the plateau value being determined mainly by the proportion of crosslinked hyaluronic acid.
  • Examples 2 and 3 show an identical course within the scope of measurement accuracy both for the course of the two modules G 'and G "and for the complex viscosity ⁇ ⁇ * ⁇
  • the memory modulus of 2439 Pa decreases at one frequency from 100 rads "1 to a value of 1327 Pa at 0.01 rads ""1 and in example 3 from 2800 Pa at 100 rads " 1 to 1382 Pa at 0.01 rads "
  • the different particle sizes of the two examples 150 ⁇ m in the example and 350 ⁇ m in Example 3) have only a very small influence on the position of the two modules.
  • the rheological measurement results show that the viscosity of the dispersion decreases rapidly even at the lowest shear stress.
  • a hyaluronic acid dispersion is therefore particularly suitable for injection, in particular for aesthetic medicine. Due to its low viscosity when subjected to shear, the dispersion liquefies so that cannulae of less than 0.2 mm in diameter (eg 0.133 mm or 0.184 mm) in diameter are sufficient to deliver an effective amount of hyaluronic acid to the site of action to inject.
  • a hyaluronic acid dispersion as described above may be injected as an arthritis drug into an arthritic joint.
  • the proportion of cross-linked hyaluronic acid from the dispersion is able to store large amounts of water. This function allows hyaluronic acid dispersion to function as a synovial fluid replacement, preventing or reducing further abrasion of cartilage, and reducing the pain caused by lining up on insufficiently lubricated cartilage.
  • a kit which contains both a hyaluronic acid dispersion according to claim 1 and a suitable application advises.
  • This may be, for example, a syringe whose diameter is optimized for the viscosity of the hyaluronic acid dispersion. It can needle inside diameter of less than 0.2 mm, in particular 18 to 22 gears are used.
  • a hyaluronic acid dispersion as described above can also be used for aesthetic and cosmetic purposes. It is ideal for injecting wrinkles, especially the sensitive lips. Due to the reduced needle cross-section of the injection needle, the puncture in the skin surface leaves almost no noticeable traces.
  • hyaluronic acid dispersions as disclosed in claim 1 of the present invention may also be used for topical application.
  • the hyaluronic acid dispersion is combined with common cosmetic raw materials.
  • two examples of cosmetic preparations are described which contain such a hyaluronic acid dispersion. The examples are not intended to be limiting, but merely exemplary understood.
  • the resulting hyaluronic acid gel can be used as a moisturizing gel for the treatment of dry skin or as a wrinkle-smoothing gel. In particular, it exerts its effect when applied to the cleansing of the face under the lip balm.
  • Example 2
  • the water is placed in a suitable container and stirred with a paddle stirrer at room temperature. Subsequently, the imidazolidinyl urea and the inulin are added. Once the solution is clear, the hyaluronic acid dispersion is added and stirred vigorously until the mixture is homogeneous. Ssend subse- the mixture at 45 0 C is heated. In a separate container, the beeswax is weighed with the polyglyceryl-3 methylglucose distearate and the Buxus Chinensis OiI and heated to 70 0 C with stirring with a paddle stirrer. Once the waxes have melted and a homogeneous mixture is formed, the parabens are added.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Materials Engineering (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Composite Materials (AREA)
  • Biochemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cosmetics (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une dispersion d'acide hyaluronique destinée à être utilisée en médecine esthétique et en orthopédie, la phase dispersée se composant de particules d'acide hyaluronique réticulées transversalement et la phase continue se composant essentiellement d'acide hyaluronique linéaire.
EP07786333A 2007-07-25 2007-07-25 Dispersion d'acide hyaluronique, sa préparation et son application Withdrawn EP2170961A1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2007/006609 WO2009021526A1 (fr) 2007-07-25 2007-07-25 Dispersion d'acide hyaluronique, sa préparation et son application

Publications (1)

Publication Number Publication Date
EP2170961A1 true EP2170961A1 (fr) 2010-04-07

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Family Applications (1)

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EP07786333A Withdrawn EP2170961A1 (fr) 2007-07-25 2007-07-25 Dispersion d'acide hyaluronique, sa préparation et son application

Country Status (4)

Country Link
US (1) US20110166530A1 (fr)
EP (1) EP2170961A1 (fr)
CA (1) CA2658681A1 (fr)
WO (1) WO2009021526A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013185934A1 (fr) 2012-06-15 2013-12-19 Merz Pharma Gmbh & Co. Kgaa Procédé de préparation d'une composition à base d'acide hyaluronique
WO2017001057A1 (fr) 2015-06-30 2017-01-05 Merz Pharma Gmbh & Co. Kgaa Procédé de préparation de composition à base d'acide hyaluronique

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR112015015788A2 (pt) * 2012-12-31 2017-07-11 Jrx Biotechnology Inc formulações farmacêuticas de nano-emulsão tópicas líquidas
US20150283080A1 (en) * 2014-04-03 2015-10-08 Pankaj Modi Stabilized dermatological delivery system for active ingredient compositions for topical administration to the skin
US11260018B2 (en) 2015-09-17 2022-03-01 Jrx Biotechnology, Inc. Approaches for improving skin hydration and moisturization
CN110621355B (zh) * 2017-02-28 2022-01-21 Cg生物技术有限公司 皮肤注入用组合物
IL319490B1 (en) * 2025-03-09 2026-03-01 H Zingboim Cosmetics Products Ltd Preparations of miniaturized cross-linked hyaluronic acid and their uses to improve skin appearance

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Publication number Priority date Publication date Assignee Title
US5143724A (en) * 1990-07-09 1992-09-01 Biomatrix, Inc. Biocompatible viscoelastic gel slurries, their preparation and use
FR2733427B1 (fr) * 1995-04-25 2001-05-25 W K Et Associes Compositions biphasiques injectables renfermant de l'acide hyaluronique, notamment utiles en chirurgies reparatrice et esthetique
US20030211166A1 (en) * 2001-07-31 2003-11-13 Yamamoto Ronald K Microparticulate biomaterial composition for medical use
FR2819722B1 (fr) * 2001-01-19 2006-11-24 Corneal Ind Utilisation de l'acide hyaluronique ou d'au moins l'un de ses sels dans le cadre d'un traitemnet chirurgical de la presbytie
FR2865737B1 (fr) * 2004-02-03 2006-03-31 Anteis Sa Gel reticule biocompatible

Non-Patent Citations (1)

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Title
See references of WO2009021526A1 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013185934A1 (fr) 2012-06-15 2013-12-19 Merz Pharma Gmbh & Co. Kgaa Procédé de préparation d'une composition à base d'acide hyaluronique
WO2017001057A1 (fr) 2015-06-30 2017-01-05 Merz Pharma Gmbh & Co. Kgaa Procédé de préparation de composition à base d'acide hyaluronique

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Publication number Publication date
WO2009021526A1 (fr) 2009-02-19
CA2658681A1 (fr) 2009-02-19
US20110166530A1 (en) 2011-07-07

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