EP2193228A2 - Filament a base d'acide hyaluronique sous forme acide libre et son procede d'obtention - Google Patents
Filament a base d'acide hyaluronique sous forme acide libre et son procede d'obtentionInfo
- Publication number
- EP2193228A2 EP2193228A2 EP08839182A EP08839182A EP2193228A2 EP 2193228 A2 EP2193228 A2 EP 2193228A2 EP 08839182 A EP08839182 A EP 08839182A EP 08839182 A EP08839182 A EP 08839182A EP 2193228 A2 EP2193228 A2 EP 2193228A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- filament
- hyaluronic acid
- solution
- water
- acid
- 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- Withdrawn
Links
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- 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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J7/00—Chemical treatment or coating of shaped articles made of macromolecular substances
- C08J7/04—Coating
- C08J7/06—Coating with compositions not containing macromolecular substances
- C08J7/065—Low-molecular-weight organic substances, e.g. absorption of additives in the surface of the article
-
- D—TEXTILES; PAPER
- D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
- D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
- D01D5/00—Formation of filaments, threads, or the like
- D01D5/06—Wet spinning methods
-
- D—TEXTILES; PAPER
- D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
- D01F—CHEMICAL FEATURES IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS; APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OF CARBON FILAMENTS
- D01F11/00—Chemical after-treatment of artificial filaments or the like during manufacture
-
- D—TEXTILES; PAPER
- D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
- D01F—CHEMICAL FEATURES IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS; APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OF CARBON FILAMENTS
- D01F9/00—Artificial filaments or the like of other substances; Manufacture thereof; Apparatus specially adapted for the manufacture of carbon filaments
-
- D—TEXTILES; PAPER
- D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
- D06M—TREATMENT, NOT PROVIDED FOR ELSEWHERE IN CLASS D06, OF FIBRES, THREADS, YARNS, FABRICS, FEATHERS OR FIBROUS GOODS MADE FROM SUCH MATERIALS
- D06M13/00—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment
- D06M13/10—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment with compounds containing oxygen
- D06M13/184—Carboxylic acids; Anhydrides, halides or salts thereof
- D06M13/1845—Aromatic mono- or polycarboxylic acids
-
- D—TEXTILES; PAPER
- D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
- D06M—TREATMENT, NOT PROVIDED FOR ELSEWHERE IN CLASS D06, OF FIBRES, THREADS, YARNS, FABRICS, FEATHERS OR FIBROUS GOODS MADE FROM SUCH MATERIALS
- D06M15/00—Treating fibres, threads, yarns, fabrics, or fibrous goods made from such materials, with macromolecular compounds; Such treatment combined with mechanical treatment
- D06M15/01—Treating fibres, threads, yarns, fabrics, or fibrous goods made from such materials, with macromolecular compounds; Such treatment combined with mechanical treatment with natural macromolecular compounds or derivatives thereof
- D06M15/03—Polysaccharides or derivatives thereof
-
- D—TEXTILES; PAPER
- D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
- D06M—TREATMENT, NOT PROVIDED FOR ELSEWHERE IN CLASS D06, OF FIBRES, THREADS, YARNS, FABRICS, FEATHERS OR FIBROUS GOODS MADE FROM SUCH MATERIALS
- D06M15/00—Treating fibres, threads, yarns, fabrics, or fibrous goods made from such materials, with macromolecular compounds; Such treatment combined with mechanical treatment
- D06M15/01—Treating fibres, threads, yarns, fabrics, or fibrous goods made from such materials, with macromolecular compounds; Such treatment combined with mechanical treatment with natural macromolecular compounds or derivatives thereof
- D06M15/15—Proteins or derivatives thereof
-
- D—TEXTILES; PAPER
- D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
- D06M—TREATMENT, NOT PROVIDED FOR ELSEWHERE IN CLASS D06, OF FIBRES, THREADS, YARNS, FABRICS, FEATHERS OR FIBROUS GOODS MADE FROM SUCH MATERIALS
- D06M15/00—Treating fibres, threads, yarns, fabrics, or fibrous goods made from such materials, with macromolecular compounds; Such treatment combined with mechanical treatment
- D06M15/19—Treating fibres, threads, yarns, fabrics, or fibrous goods made from such materials, with macromolecular compounds; Such treatment combined with mechanical treatment with synthetic macromolecular compounds
- D06M15/21—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds
- D06M15/227—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds of hydrocarbons, or reaction products thereof, e.g. afterhalogenated or sulfochlorinated
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
- C08J2305/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
-
- D—TEXTILES; PAPER
- D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
- D06M—TREATMENT, NOT PROVIDED FOR ELSEWHERE IN CLASS D06, OF FIBRES, THREADS, YARNS, FABRICS, FEATHERS OR FIBROUS GOODS MADE FROM SUCH MATERIALS
- D06M16/00—Biochemical treatment of fibres, threads, yarns, fabrics, or fibrous goods made from such materials, e.g. enzymatic
-
- D—TEXTILES; PAPER
- D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
- D06M—TREATMENT, NOT PROVIDED FOR ELSEWHERE IN CLASS D06, OF FIBRES, THREADS, YARNS, FABRICS, FEATHERS OR FIBROUS GOODS MADE FROM SUCH MATERIALS
- D06M2101/00—Chemical constitution of the fibres, threads, yarns, fabrics or fibrous goods made from such materials, to be treated
- D06M2101/02—Natural fibres, other than mineral fibres
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
- Y10T428/2913—Rod, strand, filament or fiber
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
- Y10T428/2913—Rod, strand, filament or fiber
- Y10T428/2933—Coated or with bond, impregnation or core
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
- Y10T428/2913—Rod, strand, filament or fiber
- Y10T428/298—Physical dimension
Definitions
- the present invention relates to the field of biomaterials and relates to a method of preparation by wet spinning a hyaluronic acid-based filament, especially soluble in water.
- the invention also relates to a filament based on hyaluronic acid, said filament having swelling properties in water and physiological fluids and being otherwise able to solubilize in water under certain conditions.
- the invention also relates to the use of the hyaluronic acid-based filament thus obtained for the production of various biomaterials.
- Hyaluronic acid is a major constituent of connective tissue. It was discovered in bovine vitreous humor in 1934 by Karl Meyer [2] but its chemical structure could only be determined in the 1950s [3, 4] (numerals in square brackets refer to Bibliographical references at the end of the description).
- Hyaluronic acid is a polyelectrolyte, that is to say a polymer bearing ionizable groups capable of dissociating in polar solvents, to form a charged polymer chain surrounded by more or less mobile counter ions.
- the presence of charges gives the polyelectrolyte solutions remarkable physicochemical properties corresponding to many applications.
- Polyelectrolytes are used for their rheological properties as thickeners or gelling agents, especially in cosmetics [1]. They are also used for their adsorption properties at the interfaces.
- hyaluronic acid is used for viscosupplementation [5], the injection of hyaluronic acid into the joint with the aim of restoring the synovial fluid homeostasis by improving its rheological properties and promoting an endogenous production of hyaluronic acid.
- the properties of hyaluronic acid have also been used in ophthalmology [6] It is used in gel form, as a protective agent for eye cells when in contact with surgical instruments and implants, during surgery. Interventions in microsurgery of the eye.
- the main HA formulations marketed for this type of application are Healon® (Advanced Medical Optics, USA), Opegan® and OpeganHi® (Santen Pharmaceuticals, Japan)
- hyaluronic acid plays a key role in the hydration of the skin. It interacts with the collagen to give the cells a certain rigidity contributing to the suppleness of the skin and, by associating with the proteoglycans of the skin, the hyaluronic acid forms a network able to prevent the passage of the macromolecules (often toxic ) and to facilitate that of small electrolytes and water.
- hyaluronic acid is used in the cosmetic field for the formulation of creams or gels.
- a wet-spinning process of hyaluronic acid was developed in the 1960s and 1970s to allow the preparation of hyaluronic acid films with an oriented structure [7,8,9].
- the method is the adaptation of a protocol and a device developed for the preparation of DNA samples.
- a solution of potassium hyaluronate (2.5 to 3 mg / ml in a solution of 0.1M KCl) is extruded continuously through a die having 720 channels.
- cylindrical cylinders each having a diameter of 70 ⁇ m and a length of 1.5 mm.
- the potassium hyaluronate solution is extruded into a bath containing 75-80% ethyl alcohol in 0.1M KCl.
- the potassium hyaluronate fibers precipitate and are then bundled and wound on a rotating cylinder. Said fibers are then dried which leads to the formation of a film by coalescence.
- Short fibers (nanofibres) of hyaluronic acid, grouped in membranes, have also been obtained by the technique of "electro-spinning” and “blowing-assisted electro-spinning” [10,11], The processes mentioned do not make it possible to obtain hyaluronic acid filaments but only membranes made up of networks of nanofibers, that is to say fibers of very short length.
- materials based on hyaluronic acid fibers have been obtained by crosslinking hyaluronic acid in the presence of crosslinking agents of the carbodiimide or epoxide type (crosslinking agents, a non-exhaustive list of which is for example cited in the document US 2007066816).
- crosslinking agents of the carbodiimide or epoxide type
- the present invention proposes to overcome the aforementioned disadvantages presented by the known materials based on hyaluronic acid.
- Its primary objective is to provide a new process for producing a hyaluronic acid material in the form of a continuous filament which is free of a chemical crosslinking agent.
- filament is defined in the sense of the invention as a continuous unit fiber of very great length, being not normally interrupted during its manufacturing process, the length of said filament being measured in meters or at least tens of centimeters.
- the invention relates to a method of preparation by wet-spinning a filament based on hyaluronic acid in free (or protonated) acid form, said process being characterized in that it comprises the following steps: a) preparing a spinnable aqueous solution of hyaluronic acid or a salt of hyaluronic acid, preferably a solution of sodium hyaluronate; b) extruding said solution through an extrusion die; c) forming the filament by passing the extruded solution in a bath of concentrated acetic acid, the concentration of which is sufficiently high to coagulate the extruded solution in the form of a coagulated filament, stretching and drying.
- spinnable solution a solution whose characteristics, in particular rheological, make it capable of being extruded continuously.
- the formation of the filament is done by coagulation.
- the hyaluronic acid solution or the hyaluronic acid salt, which is extruded through the die, is progressively set in mass as it passes through the coagulation bath, the coagulating agent of which is the concentrated solution of acetic acid.
- acetic acid is concentrated to more than 80%, preferably more than 90%. At this concentration, hyaluronic acid is no longer soluble.
- the diffusion of the acetic acid solution in the extruded solution makes it possible to pass the hyaluronic acid from the liquid state to a state of physical hydrogel, in the form of a hyaluronic acid / acetic acid complex, up to obtaining a continuous filament whose section is completely coagulated, stretching and drying giving said filament its mechanical characteristics making it easily manipulated.
- acetic acid causes its hydrolysis on the one hand hyaluronic acid and on the other hand an acetate which is soluble in the acid solution concentrated acetic acid; in this way, a physical hydrogel in the form of a hyaluronic acid complex in free acid / acid form is obtained in the same manner, starting from a solution of hyaluronic acid or a hyaluronic acid salt. acetic.
- the spinnable solution is at a concentration of at least 0.8% by weight of hyaluronic acid or the equivalent weight of the hyaluronic acid salt. Below this concentration, the viscosity of the solution is insufficient to allow continuous extrusion.
- it is at a concentration of the order of 1 to 2% by weight of hyaluronic acid. Of course the concentration may vary depending on the diameter of the die used.
- the preparation of the spinnable solution consists in dissolving in water a given quantity of sodium hyaluronate in order to obtain the desired concentration, then in degassing the solution obtained, in order to eliminate the dissolved gases which can generate bubbles during the formation of the filament.
- the draw ratio may be low, for example from 1.05 to 1.10, being in this case carried out on the coagulated filament, during drying, in order to exert a sufficient tensioning of said filament to maintain its geometry. and avoid any deformation during travel until winding.
- This stretching possible because of the excellent viscoelastic properties of the solutions, in particular of sodium hyaluronate, makes it possible to adjust the diameter of the filament and its mechanical properties.
- the drying is generally complete, so as to obtain a filament which is exclusively composed of hyaluronic acid in free acid form and a small proportion of water, of the order of 8 to 12% by weight when it is conditioned in a normal atmosphere. More intensive drying would destroy the hyaluronic acid / acetic acid / water complex by removing acetic acid and water. Nevertheless, the drying may possibly be partial either to obtain a filament free of acetic acid but having a greater proportion of water or to obtain a filament retaining a certain proportion of acetic acid in the context of applications in which the presence of this component is not crippling.
- the water content of 8 to 12% is the usual water content of a polysaccharide such as hyaluronic acid in the dry state when it is in the non-ionized form, and in this case in free acid form.
- a polysaccharide such as hyaluronic acid in the dry state when it is in the non-ionized form, and in this case in free acid form.
- any polysaccharide in ionized form, especially in saline form contains under the same conditions from 16 to 18% water.
- the low water content of the hyaluronic acid filament in free acid form has important consequences on its properties, especially mechanical properties.
- the filament obtained directly by the aforementioned method can hydrate and therefore swell in contact with water or physiological media; it remains soluble in water, under conditions which are in particular a function of its crystallinity and therefore of the stretching rate to which it has been subjected.
- the step of forming the hyaluronic acid filament in free acid form is followed by a step of coating said filament with a compound capable of slowing down its hydration, and therefore the swelling and solubilization of the filament, in water or in a physiological medium.
- the coating compound remains on the surface and does not diffuse deeply into the filament.
- the coating is carried out by passing the filament through a coating bath, for example containing from 0.10 to 10% by weight of the coating compound.
- Said coating compound is, in one embodiment, a natural macromolecule such as chitosan or collagen. Since these natural polymers carry ionic sites, an electrostatic interaction occurs with polyanion / polycation-type hyaluronic acid, which increases the interaction between the coating compound and the filament. Moreover, in this case, as indeed in that of a polymer-based coating having no ionic charges, hydrogen bonds and hydrophobic interactions develop.
- the filament coating compound is a fatty compound of vegetable or animal origin, for example a vegetable wax deposited in the molten state.
- the filament active principles, which are then able to be salted out when the filament is in contact with a liquid medium, in particular a physiological medium.
- This inclusion is obtained by dipping the filament in an impregnating bath containing said active ingredients, the porosity of the filament allowing them to diffuse inwardly of the filament in the inter-fibrillar spaces, and then by drying the filament thus impregnated.
- active principles denotes all the molecules of biological interest in the field of biotechnologies, among them hormones, growth factors, interleukins, interferons, antibacterials, antifungals and biostimulants.
- the release rate of the active ingredient is a function of the interactions between said principle and the filament. The release is relatively fast if there is no interaction. On the other hand, if there are interactions, the release can be controlled either physico-chemically or by progressive biodegradation of the filament, especially in the latter case if the interactions are very strong.
- the subject of the invention is also a filament based on hyaluronic acid in free acid form obtainable by the aforementioned method.
- the base filament which is free of crosslinking chemicals, contains only hyaluronic acid in free acid form and water.
- the residual salt in particular the sodium acetate formed during of the aforementioned process, is solubilized in the concentrated acetic acid solution and is therefore not in the filament.
- the absence of crosslinking agents guarantees a better biocompatibility since said agents have a certain toxicity and thus induce inflammatory reactions in vivo.
- the filaments of the invention have, in the dry state, a water content of 8 to 12%. They have interesting swelling properties in physiological conditions. This makes them very good candidates for filling wrinkles.
- the subject of the invention is also a coated filament based on hyaluronic acid which superficially comprises a coating of a compound capable of reducing its hydration, for example chitosan or collagen, or a fatty substance of animal or vegetable origin, in particular a wax of vegetable origin.
- a compound capable of reducing its hydration for example chitosan or collagen, or a fatty substance of animal or vegetable origin, in particular a wax of vegetable origin.
- the subject of the invention is also a filament based on hyaluronic acid in free acid form which comprises active principles included in its inter-fibrillar spaces.
- the invention also relates to the use of the hyaluronic acid-based filament in free acid form in cosmetics, in particular for filling wrinkles.
- Another aspect relates to the use of the hyaluronic acid filament in free acid form of the invention for developing textile materials, for example nonwovens, for the manufacture of healing dressings.
- FIG. 1 represents the hyaluronic acid filament in free acid form according to the invention, seen with the aid of an optical microscope
- FIG. 2 shows the structure of the filament according to the invention, as observed with the aid of a scanning electron microscope
- FIG. 3 represents the strain / stress curve obtained after a tensile test at 2 mm / min on a filament according to the invention, which is not very stretched
- 4 represents the images obtained by X-ray diffraction for a macrofilament: unstretched (FIG 4a), stretched (FIG 4b) and very stretched (FIG 4c).
- the present invention relates to a method of preparation by wet spinning of a continuous filament based on hyaluronic acid in free or protonated acid form, from a spunable aqueous solution of hyaluronic acid or a sodium salt.
- hyaluronic acid preferably sodium hyaluronate.
- hyaluronic acid should be understood as hyaluronic acid in free or protonated acid form.
- a quantity of sodium hyaluronate is dissolved in water to obtain a viscous solution capable of spinning on its own, without dripping. It is noted that below 0.8% by weight, the solutions are not sufficiently viscous. For concentrations of the order of 1 to 2%, the solutions have a viscoelasticity such that they spin with a spatula.
- concentration of sodium hyaluronate is chosen according to the diameter of the extrusion die. In an experimental setting, when the extrusion die is a fine needle whose diameter is of the order of 0.8 mm, excessive viscosities prevent the passage of the solution through the die, in which case in the examples below. Below are preferred 1% by weight solutions of sodium hyaluronate.
- the solution used is subjected to a degassing step; in fact, the gases dissolved in the solutions form small bubbles which can be at the origin of embrittlement of the filament. Degassing is all the more important and difficult as the solutions are viscous.
- the spinnable solution thus prepared is extruded through an extrusion die, immersed in a coagulation bath containing a coagulating agent, stretched and dried and the obtained filament is received.
- the extrusion conditions in particular the extrusion rate, must allow the formation of a coagulated filament of constant diameter.
- the coagulation bath is a concentrated solution of acetic acid. The concentration of this acetic acid is sufficiently high to obtain that its progressive diffusion in the extruded hyaluronic acid solution makes it possible to pass hyaluronic acid from the liquid state to the state of a physical hydrogel, probably in the form of hyaluronic acid / acetic acid / water complex, to obtain a filament whose cross-section transverse is completely coagulated. It is acetic acid concentrated to more than 80%, preferably more than 90%.
- the extrusion was carried out using a syringe equipped with a RAZEL R-99E syringe pump and a needle acting as an extrusion die, having a diameter of the order of 0, 8 mm.
- the extrusion rate was between 1, 2 and 15 cm / min.
- the duration of the coagulation is controlled in three ways: by the speed of travel of the filament in the bath on the one hand, by the volume of solution contained in the reactor containing the coagulation bath on the other hand and finally by the path carried out by the filament inside this reactor.
- the residence time must be sufficient for the filament to be completely coagulated.
- the drawing is carried out using a rotating motorized system, which pulls the filament at a speed above the extrusion speed and which optionally receives it.
- the draw ratio is the ratio between the speed in linear meter of said rotary system and the extrusion rate in linear meter. Stretching can occur on the coagulated filament; in this case, the draw ratio is small, of the order of a few percent, mainly for maintaining the geometry of the wire during its movement until it is received.
- Stretching can take place immediately at the die outlet on the extruded solution that has not yet been coagulated and possibly partly on the solution extruded during coagulation; in this case, the draw ratio is much greater, which may be of the order of 2 or even greater than 2, this drawing being mainly intended to adjust the diameter of the filament and its mechanical properties.
- Drying by any suitable means, is intended to remove excess coagulation bath and reduce the proportion of acetic acid and water in the filament. During total drying, the acetic acid is completely removed and the resulting filament contains only hyaluronic acid and water, with a water content of 8 to 12%.
- the mechanical characteristics of the filament obtained are a function of the drying conditions and the degree of stretching.
- the crystallinity rate of the filament evolves as the draw ratio.
- the filament which contains only hyaluronic acid and water, can hydrate on contact with water or physiological solutions, with subsequent swelling. It remains soluble in water, under varying conditions depending on its manufacturing parameters.
- the hyaluronic acid filament undergoes a complementary coating step with a compound capable of slowing the hydration, and therefore the swelling and the solubilization of the filament, in water or in a physiological medium such as: blood, lymphatic or lacrimal fluid, etc.
- Said coating compound is, in one embodiment, a natural macromolecule such as chitosan or collagen.
- the coating compound of the hyaluronic acid filament is a fatty compound of vegetable or animal origin.
- the invention relates to a continuous filament based on hyaluronic acid obtainable by the above method.
- the known hyaluronic acid fibers obtained by electro-spinning have, according to WEB observations, diameters of less than 50 nm.
- the filament according to the present invention, obtained by the aforementioned method has a diameter which is generally from one hundred to several hundred micrometers. In addition, it has a length that is not limited, which may be several meters or at least several tens of centimeters.
- the hyaluronic acid-based filament of the invention is free from any chemical crosslinking agent, which makes it particularly suitable for in vivo uses in humans. It contains hyaluronic acid, water and possibly acetic acid. Preferably it contains exclusively hyaluronic acid and water, especially in the dry state with a water content of 8 to 12%.
- hyaluronic acid filament was characterized by optical microscopic observation and scanning electron microscopy, by tensile tests as well as by X-ray diffraction, as presented hereinafter.
- the average filament diameter was determined for each spinning speed using an optical microscope from four measurements taken at different locations along the length of the same filament. It turns out that the spinning speed has no influence on the diameter of the filaments.
- the diameters measured are between 120 and 170 ⁇ m. However, the diameter of the wires can vary by changing the drawing ratio and the diameter of the die.
- FIG. 1 The image of a filament according to the invention as visualized by means of an optical microscope is shown in FIG. 1. It is a hyaluronic acid filament obtained from a solution of 1% by weight of sodium hyaluronate for a spinning speed of 5.9 cm / min.
- the surface condition and fracture profile of the hyaluronic acid filaments were observed using a Hitachi S800 scanning electron microscope at 15 kV after metallization with gold-palladium.
- the filaments were ruptured by immersion in liquid nitrogen from a filament surrounded by a needle.
- the images obtained from a poorly drawn filament of hyaluronic acid obtained from a 1% by weight solution of sodium hyaluronate are shown in FIG.
- the filament appears at first to consist of several assembled fibers (Figure 2a), but the fracture surface (Figure 2b) clearly shows that the surface relief is due to folds. These folds or villi appear most certainly during the drying step. In Figure 2b, we also observe within these villi smaller objects such as fibrils that seem to align along the axis of the filament. Such "nanofibrils" have already been observed for chitosan fibers [12].
- Young's modulus, breaking strength, and elongation at break were then determined for each sample, i.e., for each spinning speed.
- FIG. 3 An example of a tensile curve is given in FIG. 3. It corresponds to the strain / stress curve obtained after a tensile test at 2 mm / min on a thread that is not very stretched, the spinning speed being 4.7 cm / cm 2. min. It is observed that after a linear elastic deformation domain, the filament undergoes a beginning of plastic deformation. 4. Crystallinity: X-ray diffraction (WAXS)
- FIG. 4 The images obtained by X-ray diffraction are given in FIG. 4 for a hyaluronic acid filament: unstretched (FIG. 4a), stretched (FIG. 4b) and very stretched (FIG. 4c). These results demonstrate the development of the crystallinity of the samples studied.
- a first intended application is the filling of wrinkles, because of their swelling capacity and their crystalline nature. The more the sample is crystalline and the more its resolubilization, especially at pH biological media such as blood (pH 7.2 to 7.4) or tears (pH 8) will be slowed down.
- Another application is the use of hyaluronic acid-based filaments for making textiles, in the form of nonwovens, fabrics or knits, especially in order to form healing dressings.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Textile Engineering (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Communicable Diseases (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Mechanical Engineering (AREA)
- Polymers & Plastics (AREA)
- Transplantation (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Dermatology (AREA)
- Inorganic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Materials For Medical Uses (AREA)
- Artificial Filaments (AREA)
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR0757957A FR2921675B1 (fr) | 2007-09-28 | 2007-09-28 | Filament a base d'acide hyaluronique et son procede d'obtention. |
PCT/FR2008/051729 WO2009050389A2 (fr) | 2007-09-28 | 2008-09-26 | Filament a base d'acide hyaluronique sous forme acide libre et son procede d'obtention |
Publications (1)
Publication Number | Publication Date |
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EP2193228A2 true EP2193228A2 (fr) | 2010-06-09 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP08839182A Withdrawn EP2193228A2 (fr) | 2007-09-28 | 2008-09-26 | Filament a base d'acide hyaluronique sous forme acide libre et son procede d'obtention |
Country Status (5)
Country | Link |
---|---|
US (2) | US8753671B2 (fr) |
EP (1) | EP2193228A2 (fr) |
BR (1) | BRPI0817567B1 (fr) |
FR (1) | FR2921675B1 (fr) |
WO (1) | WO2009050389A2 (fr) |
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JP5722217B2 (ja) | 2008-09-02 | 2015-05-20 | アラーガン・ホールディングス・フランス・ソシエテ・パール・アクシオン・サンプリフィエAllergan Holdings France S.A.S. | ヒアルロン酸および/またはその誘導体の糸、その作製方法、ならびにその使用 |
CZ2009836A3 (cs) | 2009-12-11 | 2011-06-22 | Contipro C A.S. | Derivát kyseliny hyaluronové oxidovaný v poloze 6 glukosaminové cásti polysacharidu selektivne na aldehyd, zpusob jeho prípravy a zpusob jeho modifikace |
CZ2009835A3 (cs) | 2009-12-11 | 2011-06-22 | Contipro C A.S. | Zpusob prípravy derivátu kyseliny hyaluronové oxidovaného v poloze 6 glukosaminové cásti polysacharidu selektivne na aldehyd a zpusob jeho modifikace |
ES2376680B8 (es) * | 2010-08-16 | 2013-04-30 | Nylstar, S.A. | Fibra textil cosmética, procedimiento de obtención y su empleo. |
CZ302994B6 (cs) | 2010-12-31 | 2012-02-08 | Cpn S.R.O. | Hyaluronová vlákna, zpusob jejich prípravy a použití |
CN102813961A (zh) * | 2011-06-10 | 2012-12-12 | 冯淑芹 | 一种含有亚微米级透明质酸微球的注射凝胶与制备方法 |
CZ2012136A3 (cs) | 2012-02-28 | 2013-06-05 | Contipro Biotech S.R.O. | Deriváty na bázi kyseliny hyaluronové schopné tvorit hydrogely, zpusob jejich prípravy, hydrogely na bázi techto derivátu, zpusob jejich prípravy a pouzití |
CZ2012282A3 (cs) | 2012-04-25 | 2013-11-06 | Contipro Biotech S.R.O. | Zesítovaný derivát hyaluronanu, zpusob jeho prípravy, hydrogel a mikrovlákna na jeho bázi |
CZ304651B6 (cs) | 2012-05-11 | 2014-08-20 | Contipro Biotech S.R.O. | Způsob přípravy mikrovláken, způsob výroby krytů ran, kryty ran a zařízení pro přípravu polysacharidových vláken |
CZ304512B6 (cs) | 2012-08-08 | 2014-06-11 | Contipro Biotech S.R.O. | Derivát kyseliny hyaluronové, způsob jeho přípravy, způsob jeho modifikace a použití |
CZ2012843A3 (cs) | 2012-11-27 | 2014-02-05 | Contipro Biotech S.R.O. | Nekonečná vlákna na bázi hyaluronanu, selektivně oxidovaného v poloze 6 N-acetyl-D-glukosaminové části, jejich příprava, použití, nitě, střiže, příze, textilie a způsob jejich úpravy |
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CZ304303B6 (cs) | 2012-11-27 | 2014-02-19 | Contipro Biotech S.R.O. | Vlákna založená na hydrofobizovaném hyaluronanu, způsob jejich přípravy a použití, textilie na jejich bázi a použití |
CZ2014150A3 (cs) | 2014-03-11 | 2015-05-20 | Contipro Biotech S.R.O. | Konjugáty oligomeru kyseliny hyaluronové nebo její soli, způsob jejich přípravy a použití |
CZ2014451A3 (cs) | 2014-06-30 | 2016-01-13 | Contipro Pharma A.S. | Protinádorová kompozice na bázi kyseliny hyaluronové a anorganických nanočástic, způsob její přípravy a použití |
CZ309295B6 (cs) | 2015-03-09 | 2022-08-10 | Contipro A.S. | Samonosný, biodegradabilní film na bázi hydrofobizované kyseliny hyaluronové, způsob jeho přípravy a použití |
CN104771780B (zh) * | 2015-04-09 | 2017-04-12 | 中国工程物理研究院核物理与化学研究所 | 一种用于敷料的高分子水凝胶的制备方法 |
CZ2015398A3 (cs) | 2015-06-15 | 2017-02-08 | Contipro A.S. | Způsob síťování polysacharidů s využitím fotolabilních chránicích skupin |
CZ306662B6 (cs) | 2015-06-26 | 2017-04-26 | Contipro A.S. | Deriváty sulfatovaných polysacharidů, způsob jejich přípravy, způsob jejich modifikace a použití |
KR101709608B1 (ko) * | 2015-09-03 | 2017-03-09 | (주)진우바이오 | 용융 방사에 의한 히알루론산염 파이버의 제조방법 및 이로부터 제조된 히알루론산염 파이버 |
CZ306354B6 (cs) | 2015-10-09 | 2016-12-14 | Contipro A.S. | Nekonečná vlákna typu jádro-obal zahrnující kombinaci nativního a C11-C18 acylovaného hyaluronanu nebo C11-C18 acylovaných hyaluronanů, způsob jejich přípravy a použití, střiž, příze a textilie z těchto vláken a jejich použití |
CZ308106B6 (cs) | 2016-06-27 | 2020-01-08 | Contipro A.S. | Nenasycené deriváty polysacharidů, způsob jejich přípravy a jejich použití |
CN108144119B (zh) * | 2018-01-12 | 2021-02-23 | 郑州大学 | 一种在生物镁合金表面磷灰石涂层上制备抗菌透明质酸钠及壳聚糖双分子层的方法 |
CN108660741B (zh) * | 2018-04-26 | 2020-08-11 | 海斯摩尔生物科技有限公司 | 一种抗菌壳聚糖纤维的制备方法 |
KR102245629B1 (ko) * | 2019-04-10 | 2021-04-30 | 주식회사 제네웰 | 히알루론산계 녹는 필름, 이의 제조방법 및 이에 사용되는 이형지 |
BR112023004156A2 (pt) | 2020-09-22 | 2023-04-04 | Swimc Llc | Composição de revestimento, artigo revestido, e, método para produzir uma composição de revestimento |
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US7662332B2 (en) * | 2003-10-01 | 2010-02-16 | The Research Foundation Of State University Of New York | Electro-blowing technology for fabrication of fibrous articles and its applications of hyaluronan |
US7323425B2 (en) * | 2004-08-27 | 2008-01-29 | Stony Brook Technology And Applied Research | Crosslinking of hyaluronan solutions and nanofiberous membranes made therefrom |
-
2007
- 2007-09-28 FR FR0757957A patent/FR2921675B1/fr not_active Expired - Fee Related
-
2008
- 2008-09-26 US US12/680,257 patent/US8753671B2/en not_active Expired - Fee Related
- 2008-09-26 EP EP08839182A patent/EP2193228A2/fr not_active Withdrawn
- 2008-09-26 WO PCT/FR2008/051729 patent/WO2009050389A2/fr active Application Filing
- 2008-09-26 BR BRPI0817567-5A patent/BRPI0817567B1/pt not_active IP Right Cessation
-
2014
- 2014-05-05 US US14/269,315 patent/US9044410B2/en not_active Expired - Fee Related
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Also Published As
Publication number | Publication date |
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FR2921675B1 (fr) | 2010-03-19 |
US9044410B2 (en) | 2015-06-02 |
US20100310631A1 (en) | 2010-12-09 |
BRPI0817567A2 (pt) | 2015-04-07 |
WO2009050389A2 (fr) | 2009-04-23 |
WO2009050389A3 (fr) | 2009-11-26 |
BRPI0817567B1 (pt) | 2018-07-24 |
US20140242146A1 (en) | 2014-08-28 |
US8753671B2 (en) | 2014-06-17 |
FR2921675A1 (fr) | 2009-04-03 |
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