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WO2014064633A1 - Processus de préparation de gel réticulé - Google Patents

Processus de préparation de gel réticulé Download PDF

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Publication number
WO2014064633A1
WO2014064633A1 PCT/IB2013/059608 IB2013059608W WO2014064633A1 WO 2014064633 A1 WO2014064633 A1 WO 2014064633A1 IB 2013059608 W IB2013059608 W IB 2013059608W WO 2014064633 A1 WO2014064633 A1 WO 2014064633A1
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Prior art keywords
salt
crosslinking
process according
polysaccharide
gel
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Ceased
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PCT/IB2013/059608
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English (en)
Inventor
Emeline CHARTON
Stéphane MEUNIER
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Teoxane SA
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Teoxane SA
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Filing date
Publication date
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Publication of WO2014064633A1 publication Critical patent/WO2014064633A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B15/00—Preparation of other cellulose derivatives or modified cellulose, e.g. complexes
    • C08B15/005—Crosslinking of cellulose derivatives
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B31/00—Preparation of derivatives of starch
    • C08B31/003—Crosslinking of starch
    • 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
    • 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
    • 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
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C08J3/075—Macromolecular gels
    • 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
    • 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

Definitions

  • the present invention aims to provide a process for preparing hydrogels based on a crosslinked polysaccharide, and preferably on hyaluronic acid or a salt thereof.
  • Hyaluronic acid which is naturally present in the skin, is known for its viscoelastic properties and also its very high propensity to absorb water. Its properties contribute to a large extent to the elasticity of the skin.
  • hyaluronic acid is in particular used for filling wrinkles and for reducing, or even eliminating, local weakening of the structure of the dermis represented by a wrinkle, generally via direct injection into the dermis, at the wrinkle under consideration.
  • hyaluronic acid is essentially used in the form of a crosslinked gel given the increased resistance to degradation and to heat, and therefore to sterilization, of this particular form.
  • crosslinked hyaluronic acid gels can be obtained by various preparation processes. Generally, these processes require two main steps, the first consisting in hydrating the hyaluronic acid so as to convert it into an aqueous gel and the second aimed at crosslinking said aqueous gel in the presence of an agent capable of inducing crosslinking thereof (also referred to as "crosslinking agent").
  • the invention aims precisely to provide a process for obtaining crosslinked gels having particularly advantageous mechanical properties.
  • the present invention relates to a process for preparing a crosslinked gel of at least one polysaccharide or a salt thereof, comprising at least the steps consisting in:
  • step a) providing an aqueous gel comprising at least said polysaccharide(s) in a noncrosslinked form, combined with at least one crosslinking agent; b) crosslinking the mixture obtained at the end of step a) and, where appropriate;
  • crosslinking step b) is carried out in a medium supplemented with at least one alkali halide salt present in a content of between 0.5% and 20% by weight relative to the total weight of the aqueous gel of step a).
  • the invention results from the unexpected observation by the inventors that the presence of an alkali halide salt during the performing of the crosslinking reaction makes it possible to significantly improve the rheo logical properties of the crosslinked gel.
  • a process in accordance with the invention is also advantageous in that it makes it possible to obtain a gel which is crosslinked using a small amount of crosslinking agent but which, on the other hand, has rheo logical properties equivalent to those shown by a crosslinked gel obtained with a conventional crosslinking process using a larger amount of crosslinking agent.
  • a process in accordance with the invention thus makes it possible to limit the amount of crosslinking agent to be introduced into the crosslinking reaction, and therefore to limit the amount of residual crosslinking agent, after the crosslinking reaction, which those skilled in the art seek to eliminate as much as possible, in particular by means of subsequent purification steps.
  • the alkali halide salt required according to the invention therefore appears to act as an active agent stimulating the crosslinking reaction.
  • skin encompasses the skin of the face, of the neck, of the neck line, of the hands, of the scalp, of the abdomen and/or of the legs, but also the lips.
  • a process of the invention may also comprise a step d) of stopping the crosslinking, which consists in exposing the crosslinked gel to conditions favourable to stopping the crosslinking thereof, it being possible for this step to be carried out before, jointly with or after the recovering step c).
  • step d) is carried out before step c).
  • the crosslinked gel obtained at the end of the implementation of a process in accordance with the invention is a single-phase gel and more particularly a predominantly elastic, viscoelastic gel, i.e. a gel with a decreased capacity, or even devoid of capacity, to flow in the absence of stresses other than its own weight.
  • polysaccharide is intended to mean any polymer consisting of several monosaccharides linked together by O-glycoside bonds and having the general formula: -[C x (H 2 0) y )] n -.
  • noncrosslinked is intended to denote an aqueous gel of polysaccharides which is not crosslinked or not transformed, i.e. a solution of polysaccharides of which the chains of the polymer(s) are not connected to one another by strong or covalent bonds.
  • a polysaccharide in accordance with the invention is more particularly selected from the viewpoint of the properties that it is desired to see the crosslinked gel obtained according to the invention display. More particularly, such a polysaccharide must have good biocompatibility.
  • a physiologically acceptable polysaccharide or polysaccharide salt may be of natural or synthetic origin.
  • the polysaccharides suitable for the invention may in particular be chosen from chondroitin sulphate, keratan, keratan sulphate, heparin, heparin sulphate, xanthan, carrageenan, hyaluronic acid, chitosan, cellulose and its derivatives, alginate, starch, dextran, pullulan, galactomannan, and biologically acceptable salts thereof.
  • polysaccharide salts in accordance with the invention are more particularly chosen from physiologically acceptable salts, such as the sodium salt, the potassium salt, the zinc salt, the silver salt, and a mixture thereof, preferably the sodium salt.
  • physiologically acceptable salts such as the sodium salt, the potassium salt, the zinc salt, the silver salt, and a mixture thereof, preferably the sodium salt.
  • a polysaccharide or polysaccharide salt according to the invention has a high molecular weight, preferably an average molecular weight greater than or equal to 50 000 Da, or even greater than 3 MDa according to the application under consideration.
  • the hyaluronic acid used for obtaining a composition according to the invention can have an average molecular weight ranging from 50 000 to 10 000 000 Daltons, preferably from 500 000 to 4 000 000 Daltons.
  • a particularly preferred polysaccharide is hyaluronic acid (HA) or a salt thereof, preferably sodium hyaluronate (NaHA).
  • the polysaccharide(s) may be used in a process according to the invention in a content of between 0.5% and 20% by weight, relative to the total weight of the aqueous gel of step a).
  • the content of hyaluronic acid is between 5% and 15% by weight relative to the total weight of the aqueous gel of step a).
  • crosslinking agent is intended to mean any compound capable of inducing crosslinking between the various polysaccharide chains.
  • a crosslinking agent in accordance with the invention is chosen from crosslinking agents, in particular bifunctional or multifunctional epoxide crosslinking agents, such as butanediol diglycidyl ether (BDDE), diepoxyoctane or l,2-bis(2,3- epoxypropyl)-2,3-ethylene, and crosslinking agents of polyamine type, such as hexamethylenediamine or l,6-diaminohexane-l ,6-hexanediamine (HMD A), endogenous polyamines such as spermine, spermidine or putrescine, and mixtures thereof.
  • crosslinking agents in particular bifunctional or multifunctional epoxide crosslinking agents, such as butanediol diglycidyl ether (BDDE), diepoxyoctane or l,2-bis(2,3- epoxypropyl)-2,3-ethylene
  • crosslinking agents of polyamine type such as hexamethylenediamine
  • a crosslinking agent in accordance with the invention is butanediol diglycidyl ether (BDDE).
  • BDDE butanediol diglycidyl ether
  • the crosslinking agent(s) can be used in a process according to the invention in a content of between 0.1 mol% and 30 mol%, preferably between 0.5 mol% and 20 mol%, relative to the total number of moles of disaccharide units forming the monomer of the hyaluronic acid present in the aqueous gel of step a).
  • an alkali halide salt can be used during the step of crosslinking a polysaccharide as an active agent stimulating this crosslinking reaction.
  • alkali halide salt is intended to denote an ionic salt which assembles two types of ions, one being an alkali ion, the other being a non- ion, necessarily representing a halogen atom.
  • the halogen atom may be chosen from fluorine, chlorine, bromine and iodine, and is preferably represented by chlorine.
  • an alkali halide salt according to the invention can be chosen from the sodium salts, the potassium salts, the lithium salts, the caesium salts, and a mixture thereof, and better still is represented by a sodium salt.
  • an alkali halide salt according to the invention may be
  • the alkali halide salt(s) may be used in a process according to the invention in a minimum content of greater than or equal to 0.5% by weight, preferably greater than or equal to 1% by weight, relative to the total weight of the aqueous gel of step a).
  • the alkali halide salt(s) may be used in a process according to the invention in a maximum content of less than or equal to 20% by weight, preferably less than or equal to 15% by weight, relative to the total weight of the aqueous gel of step a).
  • the alkali halide salt(s) is (are) used in a process according to the invention in a content of between 0.5% and 20% by weight relative to the total weight of the aqueous gel of step a).
  • the alkali halide salt(s) may be used in a process according to the invention in a content of between 1% and 15% by weight relative to the total weight of the aqueous gel of step a).
  • a process of the invention requires, firstly, providing, prior to the crosslinking step, an aqueous gel comprising at least one polysaccharide in a noncrosslinked form, combined with at least one crosslinking agent and at least one alkali halide salt.
  • aqueous gel under consideration in step a) can be obtained beforehand by bringing together, in a suitable receptacle:
  • the polysaccharide in the noncrosslinked state is therefore formulated in an aqueous medium in the gel state.
  • aqueous medium is intended to mean any liquid medium containing water and which has the property of dissolving a polysaccharide or a salt thereof.
  • aqueous medium is more particularly conditioned by the type of crosslinking envisaged, but also by the type of polymer used.
  • an aqueous medium that may be suitable can be acidic or basic.
  • the particularly preferred aqueous medium can be an alkaline medium, preferably sodium hydroxide (NaOH), more particularly a solution of sodium hydroxide at a pH above 12.
  • an aqueous gel as considered in step a) involves at least one homogenization, as indicated above.
  • the purpose of this operation is more particularly to hydrate and completely homogenize the polysaccharide in the aqueous medium and, where appropriate, the crosslinking agent and/or the alkali halide salt, and thus to contribute to optimizing the qualities of the expected crosslinked gel.
  • the homogenization is considered to be satisfactory when the solution obtained has a homogeneous colouration, without agglomerates, and a uniform viscosity. It can advantageously be carried out under mild operating conditions so as to prevent degradation of the polysaccharide chains.
  • This step is all the more important when the polysaccharide has a high molecular weight.
  • the hydration of such a compound in fact then has a tendency to generate the formation of a high- viscosity solution within which the appearance of agglomerates is commonly observed.
  • the duration of this homogenization step depends on the nature of the polysaccharide, and more particularly on its molecular weight, on its concentration, on the operating conditions within the aqueous medium and also on the homogenization device used.
  • a homogenization step according to the present invention can be carried out for a period of less than 200 minutes, preferably less than 150 minutes, or even between 5 and 100 minutes.
  • this aqueous gel can be formed by introduction, into the receptacle, of the aqueous medium, of the polysaccharide and, where appropriate, of the alkali halide salt, with simultaneous and/or consecutive homogenization of the mixture thus formed, and then addition of the crosslinking agent with simultaneous and/or consecutive homogenization.
  • this aqueous gel can be obtained by introduction, into the receptacle, of the aqueous medium, of the polysaccharide, of the crosslinking agent and, where appropriate, of the alkali halide salt, with simultaneous and/or consecutive homogenization of the mixture thus formed.
  • This second embodiment variant is advantageous in that a single homogenization step is carried out.
  • this step of forming the aqueous gel can be carried out at a temperature below 35°C, preferably at a temperature ranging from 15 to 25°C, and better still at an ambient temperature.
  • the aqueous gel of step a) is then subjected to conditions suitable for the crosslinking reaction.
  • step b) of the process of the invention This step is illustrated by step b) of the process of the invention.
  • crosslinking is to create bridges between the chains of polysaccharides, in particular of hyaluronic acid, making it possible to obtain a solid and dense three-dimensional network from a viscous solution.
  • the alkali halide salt may be present in the aqueous gel of step a).
  • the process according to the invention may also comprise a step e), intermediate between steps a) and b), consisting in adding, to the aqueous gel obtained in step a), said alkali halide salt with simultaneous and/or consecutive homogenization.
  • this step e) of adding said alkali halide salt can also be carried out at a temperature below 35°C, preferably at a temperature ranging from 15 to 25°C, and better still at an ambient temperature.
  • the alkali halide salt can be added to the aqueous gel of step a) concomitantly with the crosslinking step b), with simultaneous and/or consecutive homogenization.
  • crosslinking it requires the presence of at least one crosslinking agent, in particular as defined above.
  • the particular conditions to be retained for inducing the crosslinking reaction can depend on the nature of the polysaccharide, on its molecular weight, on the aqueous medium and on the nature of the crosslinking agent.
  • this stimulation can be acquired by bringing the mixture obtained at the end of step a) into contact with an initiating element, or else a stimulating element, such as, for example, heating, UV exposure, or even bringing said mixture into contact with a material of catalyst type.
  • a stimulating element such as, for example, heating, UV exposure, or even bringing said mixture into contact with a material of catalyst type.
  • an initiating element can be carried out by:
  • UV type for example to microwave radiation or else to infrared radiation
  • step d) can occur before, jointly with or after the step of recovering the gel c).
  • Such a step requires exposing the crosslinked gel or the gel undergoing crosslinking, or even the receptacle containing it, to conditions favourable to stopping said crosslinking, or else to conditions capable of stopping the formation of bonds between the various polysaccharide chains.
  • step d) is carried out before step c).
  • the crosslinking can be stopped:
  • the process according to the invention uses (i) sodium hyaluronate as polysaccharide in an alkaline medium, (ii) butanediol diglycidyl ether (BDDE) as crosslinking agent and (iii) NaCl as alkali halide salt in a content of between 0.5% and 20% by weight relative to the total weight of said aqueous gel of step a).
  • BDDE butanediol diglycidyl ether
  • the advantageous effect associated with the presence of the alkali halide salt permits the use of a reduced amount of crosslinking agent, compared with the conventional processes, while at the same time maintaining satisfactory mechanical properties of the crosslinked gels obtained at the end of the implementation of the process according to the invention.
  • a crosslinked gel obtained by implementing a process according to the invention may have a resulting degree of modification of between 0.1% and 15%, preferably between 0.1% and 10%, while at the same time remaining satisfactory in terms of mechanical properties.
  • the term "degree of modification” is intended to denote the ratio between the number of moles of crosslinking agent attached to the hyaluronic acid and the number of moles of hyaluronic acid forming said crosslinked gel. This quantity can in particular be measured by ID 1H NMR analysis of the crosslinked gel.
  • number of moles of hyaluronic acid is intended to mean the number of moles of repeating disaccharide units of the hyaluronic acid, the disaccharide unit being composed of D-glucuronic acid and of D-N-acetylglucosamine linked to one another by alternating beta- 1,4 and beta- 1 ,3 glycosidic linkages.
  • a process of the invention can be carried out at least partly within a specific receptacle having a deformable wall, such as, for example, a pouch, in particular the one defined in document FR 2 945 293.
  • a specific receptacle having a deformable wall such as, for example, a pouch, in particular the one defined in document FR 2 945 293.
  • the crosslinked gel obtained at the end of the process of the invention as previously described cannot be directly injectable, in particular because its polysaccharide concentration is too high and/or because of the possible presence of crosslinking agent residues, or else because of its physiological and/or pH conditions which are incompatible with use in the fields of application considered above.
  • the gel obtained at the end of the process of the invention can in particular have too great a stiffness to be injected as such into a patient.
  • a step of adding noncrosslinked hyaluronic acid may also be carried out in order to further improve the qualities of the implant, according to the know-how of those skilled in the art.
  • the gel must be physiologically formulated by virtue of the presence of salts in amounts equivalent to those of the medium injected.
  • a purification step can be carried out in order to bring the gel to a physiologically acceptable alkali halide salt concentration and/or to remove the crosslinking agent not attached to the polysaccharide and also any reaction intermediate or auxiliary agent.
  • this purification step can be carried out by means of one or more dialysis baths.
  • the resulting hydrogel can be packed into syringes under controlled atmosphere conditions, it being possible for said syringes to then undergo a sterilization step, preferably heat sterilization.
  • the NaHA is considered to be completely dissolved once all of the NaHA is hydrated and the solution completely homogeneous (absence of agglomerates and uniform colour).
  • a solution of BDDE diluted to 1/5 in a 1% sodium hydroxide solution is added to each homogeneous NaHA solution obtained at the end of the previous step, in the amount specified in Table 1.
  • reaction medium of each sample is then homogenized mechanically and each of the samples is then placed in a water bath for 3 hours, at a temperature of 52°C, in order to carry out the crosslinking.
  • the receptacles are removed from the thermostated bath and placed in a container containing refrigerated sterile water, until the temperature has cooled to 25°C (ambient temperature).
  • noncrosslinked hyaluronic acid is then incorporated into and homogenized in the gel obtained.
  • the latter are then purified by dialysis and packaged in syringes.
  • the sterilization is carried out in an autoclave (wet heat) at T° > 121°C, so as to obtain an F0 > 15 (sterilizing value).
  • Three crosslinked hyaluronic acid gels B', D' and M' are further prepared according to the above-mentioned protocol, except that the NaCl is added after the step of crosslinking reaction.
  • the weight concentration of NaCl for these crosslinked hyaluronic acid gels B', D' and M' is similar to, respectively, the weight concentration of NaCl for the crosslinked hyaluronic acid gels B, D and M.
  • Example 2 Characterization of the gels obtained in Example 1
  • D' and M' are carried out using a rheometer (Haake RS6000) equipped with a cone/plate geometry (l°/diameter 35 mm). A stress sweep is performed, and the elastic modulus G'
  • phase angle ⁇ (°) are measured at 1 Hz for a stress of 5 Pa.
  • Table 2 hereinafter represents the values of the elastic moduli G' (in Pa). By way of indication, the phase angle ⁇ (°) value is also indicated therein. Table 2
  • Example 3 Effect of the NaCl concentration, with a decrease in weight percentage of crosslinking agent
  • crosslinked hyaluronic acid gels A, E, F and G comprising different NaCl concentrations and for which the crosslinking conditions were varied by means of a modification of the amount of crosslinking agent (see Table 3 hereinafter) are prepared according to the protocol as defined in Example 1.
  • Example 1 As defined in Example 1 It may be noted that the presence of NaCl makes it possible to retain the rheo logical properties of a crosslinked gel with a lower degree of crosslinking.
  • Hyaluronic acid is dissolved at a concentration of 3% (by weight) in water supplemented with NaCl. After a homogeneous solution has been obtained, a solution containing HMDA, EDC as activator (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride) and HOBt as auxiliary coupling agent (1-hydroxybenzotriazole hydrate) is added to the hyaluronic acid solution. The volume of this solution is defined so as to obtain an overall mixture containing 2.3% of hyaluronic acid.
  • the pH of this solution is adjusted so as to obtain a pH of the overall mixture of between 5.5 and 6.5 before reaction.
  • the aqueous gel is exposed for 15 hours at 25°C.
  • the gel obtained is purified by means of several dialysis baths over a period of 48 hours and, if necessary, adjusted to physiological pH.
  • the aqueous gel obtained after washing comprises a concentration close to
  • the sterilization is carried out in an autoclave (wet heat) at T° > 121°C, so as to obtain an F0 > 15 (sterilizing value).

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Abstract

L'invention concerne un processus de préparation de gel réticulé d'au moins un polysaccharide ou d'un sel de celui-ci, lequel comprend les étapes consistant à : a) fournir un gel aqueux comprenant au moins le ou lesdits polysaccharides sous forme non réticulée, combinés à au moins un agent de réticulation ; b) réticuler le mélange obtenu à la fin de l'étape a) et ; lorsque nécessaire c) récupérer le gel réticulé formé, ladite étape de réticulation b) se faisant dans un milieu comprenant au moins un sel d'halogénure alcalin dans une teneur de 0,5 à 20 % en poids par rapport au poids total du gel aqueux de l'étape a).
PCT/IB2013/059608 2012-10-24 2013-10-24 Processus de préparation de gel réticulé Ceased WO2014064633A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR1260145A FR2997085B1 (fr) 2012-10-24 2012-10-24 Procede de preparation d'un gel reticule
FR1260145 2012-10-24

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WO2014064633A1 true WO2014064633A1 (fr) 2014-05-01

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WO2018083195A1 (fr) 2016-11-03 2018-05-11 Merz Pharma Gmbh & Co. Kgaa Procédé de préparation de charges dermiques à base d'acide hyaluronique, charges dermiques obtenues par ce procédé et leur utilisation
EP3233043B1 (fr) 2014-12-15 2019-11-06 Teoxane Procédé de préparation d'hydrogels
WO2020030629A1 (fr) 2018-08-07 2020-02-13 Merz Pharma Gmbh & Co. Kgaa Procédé de filtration dynamique d'un hydrogel réticulé
WO2022053875A1 (fr) 2020-09-09 2022-03-17 Teoxane SA Hydrogel comprenant un polysaccharide reticule et silyle et son procede d'obtention
WO2023082084A1 (fr) * 2021-11-10 2023-05-19 爱美客技术发展股份有限公司 Matériau sous forme de gel, son procédé de préparation, et son utilisation
CN116284867A (zh) * 2015-12-29 2023-06-23 高德美控股有限公司 用于生物聚合物的脱乙酰化的方法
WO2023198920A1 (fr) 2022-04-15 2023-10-19 Teoxane SA Procede de preparation d'un hydrogel
WO2023198922A1 (fr) 2022-04-15 2023-10-19 Teoxane SA Procede de preparation d'un hydrogel comprenant un polysaccharide silyle reticule
US12540219B2 (en) 2015-12-29 2026-02-03 Galderma Holding SA Method for deacetylation of biopolymers

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114349977B (zh) * 2022-01-08 2024-05-03 杭州科腾生物制品有限公司 一种透明质酸钠直线交联方法

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1986000079A1 (fr) * 1984-06-08 1986-01-03 Pharmacia Ab GEL D'ACIDE HYALURONIQUE RETICULE A UTILISER COMME SUBSTITUT DE l'HUMEUR VITREUSE
WO2000046252A1 (fr) * 1999-02-05 2000-08-10 Vitrolife Uk Limited Procede de reticulation d'acide hyaluronique avec des polymeres
US20060105022A1 (en) 2004-11-15 2006-05-18 Shiseido Co., Ltd. Process for preparing crosslinked hyaluronic acid gel
WO2006056204A1 (fr) 2004-11-24 2006-06-01 Novozymes Biopolymer A/S Methode permettant de reticuler de l'acide hyaluronique avec du divinylsulfone
US20070036745A1 (en) 2003-12-30 2007-02-15 Leshchiner Adelya K Polymeric materials, their preparation and use
US20080139796A1 (en) 2006-12-08 2008-06-12 Toshiaki Yagi Method of manufacturing gel using polysaccharides as raw materials
FR2945293A1 (fr) 2009-05-11 2010-11-12 Teoxane Procede de preparation d'un gel reticule.
WO2011023355A2 (fr) * 2009-08-27 2011-03-03 Fidia Farmaceutici S.P.A. Gels visco-élastiques utilisés en tant qu'agents de remplissage novateurs

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1986000079A1 (fr) * 1984-06-08 1986-01-03 Pharmacia Ab GEL D'ACIDE HYALURONIQUE RETICULE A UTILISER COMME SUBSTITUT DE l'HUMEUR VITREUSE
WO2000046252A1 (fr) * 1999-02-05 2000-08-10 Vitrolife Uk Limited Procede de reticulation d'acide hyaluronique avec des polymeres
US20070036745A1 (en) 2003-12-30 2007-02-15 Leshchiner Adelya K Polymeric materials, their preparation and use
US20060105022A1 (en) 2004-11-15 2006-05-18 Shiseido Co., Ltd. Process for preparing crosslinked hyaluronic acid gel
WO2006056204A1 (fr) 2004-11-24 2006-06-01 Novozymes Biopolymer A/S Methode permettant de reticuler de l'acide hyaluronique avec du divinylsulfone
US20080139796A1 (en) 2006-12-08 2008-06-12 Toshiaki Yagi Method of manufacturing gel using polysaccharides as raw materials
FR2945293A1 (fr) 2009-05-11 2010-11-12 Teoxane Procede de preparation d'un gel reticule.
WO2011023355A2 (fr) * 2009-08-27 2011-03-03 Fidia Farmaceutici S.P.A. Gels visco-élastiques utilisés en tant qu'agents de remplissage novateurs

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3233043B1 (fr) 2014-12-15 2019-11-06 Teoxane Procédé de préparation d'hydrogels
CN116284867A (zh) * 2015-12-29 2023-06-23 高德美控股有限公司 用于生物聚合物的脱乙酰化的方法
US12540219B2 (en) 2015-12-29 2026-02-03 Galderma Holding SA Method for deacetylation of biopolymers
WO2018083195A1 (fr) 2016-11-03 2018-05-11 Merz Pharma Gmbh & Co. Kgaa Procédé de préparation de charges dermiques à base d'acide hyaluronique, charges dermiques obtenues par ce procédé et leur utilisation
US11324672B2 (en) 2016-11-03 2022-05-10 Merz Pharma Gmbh & Co. Kgaa Method for preparing hyaluronic acid dermal fillers, dermal fillers obtained thereby and their use
WO2020030629A1 (fr) 2018-08-07 2020-02-13 Merz Pharma Gmbh & Co. Kgaa Procédé de filtration dynamique d'un hydrogel réticulé
WO2022053875A1 (fr) 2020-09-09 2022-03-17 Teoxane SA Hydrogel comprenant un polysaccharide reticule et silyle et son procede d'obtention
WO2023082084A1 (fr) * 2021-11-10 2023-05-19 爱美客技术发展股份有限公司 Matériau sous forme de gel, son procédé de préparation, et son utilisation
WO2023198920A1 (fr) 2022-04-15 2023-10-19 Teoxane SA Procede de preparation d'un hydrogel
WO2023198922A1 (fr) 2022-04-15 2023-10-19 Teoxane SA Procede de preparation d'un hydrogel comprenant un polysaccharide silyle reticule
FR3134577A1 (fr) 2022-04-15 2023-10-20 Teoxane SA Procede de preparation d’un hydrogel comprenant un polysaccharide silyle reticule

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