• 专利附录
  • 专利说明
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    • 专利摘要:
    The present invention relates to a method for preparing a crosslinked gel of at least one polysaccharide or a salt thereof, comprising at least the steps of: a) providing a solution formed from an aqueous medium comprising at least least said polysaccharide (s) or a salt thereof in a non-crosslinked form, at least one bi- or multi-functional epoxide crosslinking agent and at least one phosphate salt; b) crosslinking the solution of step a) and, if appropriate; c) recovering said crosslinked gel formed.
    公开号:FR3029928A1
    申请号:FR1462401
    申请日:2014-12-15
    公开日:2016-06-17
    发明作者:Francois Bourdon；Stephane Meunier
    申请人:Teoxane SA；
    IPC主号:
    专利说明:

    [0001] The present invention aims at providing a process for preparing hydrogels based on a crosslinked polysaccharide, and preferably hyaluronic acid, or a salt thereof. Naturally present in the skin, hyaluronic acid is known for its viscoelastic properties and its great propensity to absorb water. Its properties contribute largely to the elasticity of the skin. It is precisely with regard to these properties that this compound has been used for more than 10 years in many applications in the medical and cosmetic fields, such as cosmetic surgery, dental surgery, joint viscosupplementation or ophthalmology. Thus, hyaluronic acid is used in particular for filling wrinkles and for lessening or even eradicating a local slump in the structure of the dermis that is a wrinkle, generally via direct injection into the dermis, at the level of the wrinkle considered. In fact, hyaluronic acid is essentially used in the form of a crosslinked gel in view of the increased resistance of this particular form to degradation and heat, and thus to sterilization. These crosslinked gels of hyaluronic acid can be obtained by different preparation methods. In general, these processes require two main stages, the first consisting in hydrating the hyaluronic acid to transform it into an aqueous gel and the second aiming at crosslinking said aqueous gel in the presence of an agent capable of inducing its crosslinking ( also called "crosslinking agent"). By way of illustration of these methods, mention may in particular be made of those described in the documents US 2006/0105022, WO 2006/056204 or US 2007/0036745. For obvious reasons, the improvement of the mechanical properties of hydrogels, based on a crosslinked polysaccharide, objective likely to go through the improvement of the processes for preparing these hydrogels, is a constant objective. As such, FR 2 997 085 describes a process including the presence of an alkali metal halide salt, especially NaCl, when carrying out the crosslinking reaction. This alkaline halide salt makes it possible to improve the rheological properties of the crosslinked gel. The present invention aims at providing a process for obtaining crosslinked gels having even more advantageous mechanical properties.
    [0002] Unexpectedly, the inventors have found that carrying out the step of crosslinking the polysaccharide, especially hyaluronic acid, in the presence of a conventional crosslinking agent and in addition of a particular compound, provides access to to a crosslinked gel which is particularly advantageous in terms of mechanical properties and resistance to heat degradation (sterilization) and oxidative stress (by incubation with H 2 O 2), compared to gels obtained by conventional methods. Thus, the present invention relates, in a first aspect, to a process for preparing a crosslinked gel of at least one polysaccharide or a salt thereof, comprising at least the steps of: a) providing a solution (or mixture) formed of an aqueous medium comprising at least said polysaccharide (s) or one of its salts in a non-crosslinked form, at least one bi- or multi-functional epoxide crosslinking agent and at least one phosphate salt; b) crosslinking the solution of step a) and, if appropriate; C) recovering said crosslinked gel formed. Preferably, the crosslinking step b) is carried out at room temperature. More specifically, and as is apparent from the examples below, the invention results from the unexpected observation by the inventors that the presence of a phosphate salt, when carrying out the crosslinking reaction, significantly improves The rheological properties of the crosslinked gel obtained; and the properties of resistance to heat degradation (sterilization) and to oxidative stress (incubation with H 2 O 2) of the crosslinked gel obtained. Moreover, and even more unexpectedly, the inventors have observed that the presence of a phosphate salt results in effective crosslinking of the polysaccharide with very low amounts of crosslinking agent which, in the absence of said phosphate salt , do not allow the realization of effective crosslinking of the polysaccharide. This emerges in particular from Example 1 below. The presence of at least one phosphate salt during the crosslinking reaction even leads to a synergistic effect since the rheological properties of the crosslinked gel obtained can not be reproduced with crosslinked gels whose crosslinking is carried out sequentially, namely in the presence a bi- or multi-functional epoxy crosslinking agent and then a phosphate salt, or vice versa. This emerges in particular from Example 4 below. From these observations, it follows that a process according to the invention is advantageous in that it makes it possible to access a satisfactory crosslinked gel, in particular for the filling of wrinkles, by using reduced amounts of agent (s). ) epoxide crosslinking bi- or multi-functional but in contrast with rheological properties at least equivalent to those shown by a crosslinked gel obtained with a conventional crosslinking process using larger amounts of epoxy crosslinking agent bi- or multi- functional.
    [0003] A process according to the invention thus makes it possible to limit the quantity of bi- or multi-functional epoxy crosslinking agent to be introduced for carrying out the crosslinking reaction, and therefore (1) to limit the potential amount of crosslinking agent. epoxidic bi- or multi-functional residual after the crosslinking reaction of which the skilled person today seeks the maximum to overcome, in particular by means of subsequent purification steps, and (2) to reduce the rate of modification of the crosslinked polysaccharide, that is to say to get as close as possible to the polysaccharide in its natural non-crosslinked form. This emerges in particular from Example 1 below. The use of a phosphate salt in the presence of a polysaccharide has already been considered for the purpose of crosslinking or functionalizing said polysaccharide (Lack et al., 2007, Carbohydrate Research, 342: 943, Dulong et al. , 2011, Springer, Polym Bull, WO 2008/090583, WO 2009/047346 or US 5,783,691). However, none of these documents describes the unexpected effect of a phosphate salt as a "booster" in the case of a crosslinking between a polysaccharide and a bi- or multi-functional epoxide crosslinking agent.
    [0004] All of the above-mentioned advantages in connection with a process according to the present invention are all the more unexpected as no sticking reaction of the phosphate salt on the polysaccharide has been demonstrated. This is more particularly apparent from Example 1 below. According to a particular embodiment, a process of the invention may further comprise at least one step d) of homogenizing the solution (or mixture) of step a), this step being carried out previously and / or simultaneously with the crosslinking step b), preferably prior to the crosslinking step b).
    [0005] Advantageously, the crosslinked gel obtained at the end of the implementation of a process according to the invention is a viscoelastic gel which is predominantly elastic, that is to say decreased or even devoid of the faculty of 'flow in the absence of constraints other than its own weight.
    [0006] According to another of its aspects, the present invention relates to an injectable and sterile dermatological composition comprising, in a physiologically acceptable medium, at least one crosslinked gel obtained by carrying out a process according to the present invention. According to yet another of its aspects, the present invention relates to a cosmetic or dermatological composition comprising at least one crosslinked gel obtained by carrying out a process according to the present invention. According to another of its aspects, the present invention relates to a kit comprising: a packaging containing at least one dose of a crosslinked gel obtained by carrying out a process according to the present invention or a composition as defined above; and an injection device in or through the skin or a device for micro-perforation of the skin, dedicated to the administration of said dose. According to another of its aspects, the present invention relates to the use of a crosslinked gel obtained by implementing a method according to the present invention, for filling the volume defects of the skin, and in particular the filling of wrinkles. The present invention also relates to a crosslinked gel obtained by carrying out a method according to the present invention, for its use for the treatment of gingival deficiencies, in particular periodontal diseases and the associated disorders.
    [0007] The term "periodontal disease" is a generic name used to describe inflammatory diseases of the periodontium, surrounding tissues and attachment of teeth to the jaw. The periodontium consists of the cementum, periodontal ligaments and gingiva, which includes the alveolar bone and the soft tissues covering it. Periodontal disease is the leading cause of tooth loss in the adult population (Anderson's Pathology, p.2000, John M. Kissane ed., 9th ed. (1992)).
    [0008] The present invention also relates to a crosslinked gel obtained by carrying out a method according to the present invention, for its use for articulative vi ssuction. The present invention also relates to a crosslinked gel obtained by carrying out a process according to the present invention for its use for the treatment of ophthalmic disorders, in particular for the extraction of cataracts, insertion and removal of lenses. intraocular (L10). For the purposes of the present invention, the term "skin" includes the skin of the face, neck, décolleté, hands, scalp, abdomen and / or legs but also the lips. Polysaccharide By "polysaccharide" is meant any polymer consisting of several monosaccharides linked together by 0-osidic bonds and having the general formula: - [Cx (H 2 O) y)] n-.
    [0009] For the purposes of the present invention, the term "non-crosslinked" is intended to mean an aqueous gel of uncrosslinked or unconverted polysaccharides, that is to say a solution of polysaccharides whose chains of the polymer (s) do not are not connected to each other by strong or covalent bonds. A polysaccharide according to the invention is more particularly selected with regard to the properties which it is desired to manifest by the crosslinked gel obtained according to the invention. More particularly, such a polysaccharide must have good biocompatibility. Also, a polysaccharide according to the invention must have good stability over time, in particular after crosslinking, in view of its destination, namely in particular for the filling of defects in the volume of the skin, and in particular the filling of wrinkles. A polysaccharide or polysaccharide salt according to the invention is therefore physiologically acceptable and can be of natural or synthetic origin. The polysaccharides which are suitable for the invention may be chosen in particular from chondroitin sulphate, keratan, keratan sulphate, heparin, heparin sulphate, xanthan, carrageenan and hyaluronic acid (HA). chitosan, cellulose and its derivatives, alginate, starch, dextran, pullulan, galactomannan and their biologically acceptable salts. The polysaccharide salts according to 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 mixtures thereof, preferably the sodium salt. Preferably, a polysaccharide or polysaccharide salt according to the invention, or even hyaluronic acid (HA), 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 considered.
    [0010] Advantageously, a polysaccharide or polysaccharide salt according to the invention, or even hyaluronic acid, may 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).
    [0011] Bi-or multi-functional epoxy cross-linking agent By "bi- or multi-functional epoxide crosslinking agent" is meant any compound capable of inducing crosslinking between the different polysaccharide chains and comprising at least one epoxide group which is bi- or multi-functional. -functional.
    [0012] The choice of this crosslinking agent with respect to the polysaccharide to be crosslinked clearly falls within the competence of those skilled in the art. As crosslinking agent according to the present invention, mention may especially be made of epoxy crosslinking agents which are bi- or multi-functional, in particular butanediol diglycidyl ether (BDDE), diepoxy-octane, 1,2-bis- (2). , 3-epoxypropyl) -2,3-ethylene, and mixtures thereof. Preferably, a crosslinking agent according to the invention is butanediol diglycidyl ether (BDDE). Adjusting the amount of bi- or multifunctional epoxy crosslinking agent for carrying out the crosslinking reaction is also within the skill of the art. Advantageously, the molar ratio "total number of moles of polysaccharide units / number of moles of bi- or multi-functional epoxy crosslinking agent (s)" in a solution according to step a) may be between 0.005 and 1, preferably between 0.01 and 0.25. The total number of moles of polysaccharide units may preferably be the total number of moles of disaccharide units forming the hyaluronic acid monomer. Phosphate salt As indicated above, the inventors have unexpectedly observed that, in addition to the bi- or multi-functional epoxide crosslinking agent, the additional presence of at least one phosphate salt for carrying out the step of crosslinking leads to a significant improvement of the properties, in terms of rheology and resistance to degradation by heat (sterilization) and oxidative stress (by incubation with H2O2), manifested by a crosslinked gel obtained at the end of the process according to the invention. A phosphate salt according to the invention may be selected from sodium salts, potassium salts, lithium salts, cesium salts, silver salts, and mixtures thereof, preferably a sodium salt. Advantageously, a phosphate salt according to the invention may be chosen from sodium phosphate (SP), sodium triphosphate (STPP), sodium trimetaphosphate (STMP), and mixtures thereof, preferably sodium trimetaphosphate.
    [0013] Advantageously, the molar ratio "number of moles of phosphate salt (s) / total number of moles of polysaccharide units" in a solution according to step a) may be between 0.005 and 1, preferably between 0.01 and 0.01. and 0.25. Again, the total number of moles of polysaccharide units may preferably be the total number of moles of disaccharide units forming the hyaluronic acid monomer. Process according to the invention A method of the invention requires, in a first step, to have a solution formed of an aqueous medium (or aqueous gel) comprising at least one polysaccharide, or a salt thereof, under a non-crosslinked form.
    [0014] The solution considered in step a) of a process according to the present invention may be obtained beforehand by bringing into contact, within an appropriate receptacle: (i) an aqueous medium; (ii) at least one polysaccharide, or a salt thereof, in a non-crosslinked form; (iii) at least one bi- or multi-functional epoxide crosslinking agent; and (iv) at least one phosphate salt. the order of addition to the receptacle of the compounds (i) to (iv) being indifferent. According to a first variant embodiment, the solution considered in step a) of a process according to the present invention is obtained beforehand by placing, within an appropriate receptacle: (i) an aqueous medium; (ii) at least one polysaccharide, or a salt thereof, in a non-crosslinked form; then adding (iii) at least one bi- or multi-functional epoxide crosslinking agent; and (iv) at least one phosphate salt, the order of addition in the receptacle of the compounds (iii) and (iv) being indifferent, or even the addition in the receptacle of the compounds (iii) and (iv) being advantageously simultaneous. The simultaneous addition in the receptacle of compounds (iii) and (iv) involves a prior or parallel step of preparing a solution (called crosslinking solution) comprising at least the epoxide crosslinking agent (s) (s). ) bi- or multi-functional and the phosphate salt (s). According to a second variant embodiment, the solution considered in step a) of a process according to the present invention is obtained beforehand by placing, in a suitable receptacle: (i) an aqueous medium; (ii) at least one bi- or multi-functional epoxide crosslinking agent; (iii) at least one phosphate salt; then adding (iv) at least one polysaccharide, or a salt thereof, in an uncrosslinked form, the order of addition in the receptacle of the compounds (i), (ii) and (iii) being indifferent, even adding to the receptacle compounds (ii) and (iii) being advantageously simultaneous.
    [0015] The simultaneous addition in the receptacle of the compounds (ii) and (iii) involves a preliminary or parallel step of preparation of a solution (called the crosslinking solution) comprising at least the epoxidic cross-linking agent (s) ( s) bi- or multi-functional and phosphate salt (s).
    [0016] For the purpose of the present invention, the term "aqueous medium" is intended to mean any liquid medium containing water which has the property of dissolving a polysaccharide or one of its salts. The nature of the aqueous medium is more particularly conditioned with regard to the type of crosslinking envisaged, the type of crosslinking agent considered, but also the type of polysaccharide used. As such, the aqueous medium that may be suitable will be adjusted to pH according to the knowledge of the skilled person. Preferably, and especially in view of the bi- or multi-functional epoxy crosslinking agent, the aqueous medium is preferably basic. Thus, and even more preferably, the aqueous medium has a basic pH, preferably greater than 11, or even greater than 12. For example, in the case of the use of BDDE as an epoxide crosslinking agent In a bi- or multi-functional form, a particularly preferred aqueous medium may be an alkaline medium, preferably sodium hydroxide (NaOH), more particularly a sodium hydroxide solution having a pH greater than 12. Advantageously, this step of The formation of a solution according to step a) can be carried out at room temperature, preferably at a temperature below 35 ° C, and more preferably at a temperature of from 15 to 25 ° C.
    [0017] The formation of a solution as considered in step a) advantageously involves at least one homogenization, as indicated above. This step is illustrated by step d) of the process of the invention. This operation is more particularly intended to perfectly hydrate and homogenize the polysaccharide in the aqueous medium, and thus to contribute to the optimization of the qualities of the expected crosslinked gel.
    [0018] This operation also aims to homogenize the bi-or multi-functional epoxy crosslinking agent and the phosphate salt in the solution of step a), also contributing to the optimization of the qualities of the crosslinked gel expected. The homogenization is considered satisfactory when the solution obtained has a homogeneous coloration, without agglomerate and a uniform viscosity. It can advantageously be carried out under mild operating conditions to prevent degradation of the polysaccharide chains. This step is even more important when the polysaccharide has a high molecular weight. The hydration of such a compound then tends to cause the formation of a high viscosity solution in which the appearance of agglomerates is commonly observed. Step d) homogenization of the solution obtained according to step a) is carried out previously and / or in conjunction with the crosslinking step b) described below, preferably prior to the crosslinking step b).
    [0019] The duration of this homogenization step depends in particular on the nature of the polysaccharide, and more particularly on its molecular weight, its concentration, the respective contents of the various compounds used, in particular the quantities of polysaccharide (s) involved, the operating conditions within the aqueous medium and the homogenization device used.
    [0020] Adjusting the appropriate homogenization time to obtain a sufficiently homogeneous aqueous polysaccharide gel is within the general skill of those skilled in the art. The homogenization can also be broken down into several cycles, possibly with waiting times between the cycles, in particular so as to assess the quality of homogenization of the polysaccharide (s) in the aqueous medium. Preferably, a homogenization step according to the present invention may take place over a total duration of less than 200 minutes, preferably less than 150 minutes or even between 5 and 100 minutes.
    [0021] The solution of step a) is then subjected to conditions suitable for the crosslinking reaction. This step is illustrated by step b) of the process of the invention.
    [0022] Crosslinking is intended to create bridges between the polysaccharide chains, and in particular hyaluronic acid, which makes it possible to obtain a solid and dense three-dimensional network from a viscous solution. The first condition for inducing the carrying out of the crosslinking reaction in a process according to the present invention resides in the presence, in the solution of step a), of at least one bi- or multi-crosslinking epoxy crosslinking agent. functional and at least one phosphate salt. The operating conditions of the crosslinking reaction may depend in particular on the nature of the polysaccharide, its molecular weight, the nature of the bi- or multi-functional epoxy crosslinking agent and the aqueous medium. According to a first variant embodiment, the cross-linking step b) is carried out at room temperature. Preferably, and according to this variant embodiment, the crosslinking step b) can be carried out at a temperature below 35 ° C., preferably at a temperature ranging from 15 to 25 ° C., and better still from 19 to 23 ° C. C. Crosslinking at room temperature implies a crosslinking kinetics such that the crosslinking step b) can then proceed preferably over a period of between 5 hours and 336 hours (ie 2 weeks), preferably between 20 hours and 150 hours, and better between 40 hours and 100 hours.
    [0023] A faster kinetics of crosslinking, that is to say less than 5 hours, can when it is acquired by bringing into contact with a solution of step a) with at least one stimulating element, different from the bi- or multi-functional epoxy crosslinking agent and phosphate salt. The stimulating element may for example be represented by heating, UV exposure, microwave exposure, or even bringing the solution of step a) into contact with a catalyst material. The choice of such a stimulating element falls within the general knowledge of those skilled in the art. Thus, a stimulating element may consist of: the immersion of the receptacle comprising the solution of step a) in a bath containing a hot fluid, for example, whose temperature is greater than 40 ° C., preferably between 45 ° C. and 60 ° C; The exposure of the latter to radiation of certain wavelengths of the UV type, for example, to microwave or infrared radiation; irradiation of the latter by means of ionizing rays, like the process described in the document US 2008/0139796; and 5 - enzymatic crosslinking; the addition of a catalyst and / or a reaction intermediate, or even the combinations between the various elements mentioned above. Preferably, and according to the alternative embodiment where the crosslinking step b) is carried out in the presence of a stimulating element, said stimulating element consists in raising the temperature of the solution of step a). Advantageously, and according to this variant embodiment, the crosslinking step b) is carried out at a temperature above 40 ° C., preferably above 50 ° C., and more particularly between 45 and 60 ° C., and better still between 50 ° C. and 50 ° C.. and 55 ° C. The degree of crosslinking also depends on the crosslinking time imposed on the gels. The longer the time, the more important it will be, but with an optimum not to be exceeded. Thus, in the case of a crosslinking carried out in the presence of a stimulating element, in particular an increase in temperature as described above, the crosslinking step b) can advantageously be carried out over a period ranging from 30 to 300 minutes, preferably 100 to 240 minutes. According to a particularly preferred embodiment considering the use of a stimulating element, in particular represented by a rise in temperature as described above, the step b) of crosslinking is carried out at a temperature of the order of 50 to 55 ° C, for a period of 100 to 240 minutes.
    [0024] Advantageously, the crosslinking conditions are adjusted to obtain a degree of crosslinking such that the gel formed is a viscoelastic gel, or even predominantly elastic. The cessation of the crosslinking may occur previously, jointly or after the gel recovery step c). For example, the cessation of the crosslinking can be achieved by or result from: the neutralization of the pH; The dilution of the crosslinked gel; stopping the operating conditions, for example stopping radiation or heating; and / or - depletion of bi- or multi-functional epoxy crosslinking agent.
    [0025] According to a particularly preferred embodiment, the process according to the invention uses (i) sodium hyaluronate as polysaccharide in an alkaline medium, (ii) butanediol diglycidyl ether (BDDE) as crosslinking agent. epoxidic bi- or multi-functional and (iii) sodium trimetaphosphate (STMP) as the phosphate salt. As indicated above, the advantageous effect attached to the presence of the phosphate salt permits the use of reduced amount of multi-functional epoxy crosslinking agent compared to conventional processes, while maintaining mechanical and strength properties. the satisfactory degradation of the heat and oxidative stress of the crosslinked gels obtained at the end of the implementation of the process according to the invention. Thus, according to this particular embodiment, the crosslinked polysaccharide (s) included in a crosslinked gel obtained by carrying out a process according to the invention can have a modification rate. less than 10%, preferably between 0.1% and 5%, better still between 0.4% and 2.5%, and even between 0.7% and 1.6%, while remaining satisfactory in terms of mechanical properties and resistance to degradation to heat and oxidative stress. For the purposes of the present invention, the term "modification rate" is intended to mean the ratio between the number of moles of crosslinking agent attached to the polysaccharide and the number of moles of polysaccharide forming said crosslinked gel. This quantity may in particular be measured by 1 H NMR analysis of the crosslinked gel, as described in Example 1 below. By "number of moles of hyaluronic acid" is meant the number of moles of repeating disaccharide units of hyaluronic acid, the disaccharide unit being composed of D-glucuronic acid and DN-acetylglucosamine bound together by alternate glycosidic beta-1,4 and beta-1,3.
    [0026] In addition, and as is apparent from Example 1 below, the phosphate salt in a process according to the invention is also advantageous in that no additional modification of the polysaccharide related to the invention has been identified. this phosphate salt.
    [0027] Also, a crosslinked gel obtained by carrying out a process according to the present invention may have an elastic modulus (G ') of between 20 and 1000 Pa, preferably between 35 Pa and 400 Pa, associated with a phase shift angle. (Δ) less than 45 °. These parameters can in particular be measured using the protocols described below.
    [0028] According to a particular embodiment, and in order to further improve the qualities of the implant, a method according to the present invention may further comprise a step e) of adding at least one non-crosslinked polysaccharide, preferably of non-crosslinked hyaluronic acid, this step e) being carried out previously, jointly or after the recovery step c) but necessarily after the crosslinking step b). Thus, a crosslinked gel obtained by carrying out a process according to the present invention may further comprise a non-crosslinked polysaccharide, preferably uncrosslinked hyaluronic acid.
    [0029] Preferably, step e) when it is present in a process according to the invention is carried out after the recovery step c). The uncrosslinked polysaccharide, preferably uncrosslinked hyaluronic acid, may have the above characteristics.
    [0030] According to yet another particular embodiment, a method according to the present invention may further comprise a step f) of adding at least one anesthetic agent, this step f) being preferably carried out after the crosslinking step b). , or even after the purification step defined below when the latter is performed.
    [0031] The choice and the quantity of anesthetic agent are adjusted so as not to raise any risk of incompatibility with the other compounds used in a crosslinked gel according to the invention, and in particular with the polysaccharide and more particularly with the hyaluronic acid, and to be compatible with the uses under consideration. These adjustments are within the general skills of those skilled in the art. An anesthetic agent that can be used in the present invention can thus be chosen from ambucaine, amolanone, amylocaine, articaine, benoxinate, benzocaine, betoxycaine, biphenamine, bupivacaine, butacaine and butamben. , butanilican, butethamine, butoxycaine, carticain, chloroprocaine, cocaethylene, cocaine, cyclomethycaine, dibucaine, dimethysoquin, dimethocaine, diperodone, dycyclonine, ecgonidine, ecgonine, chloride ethyl, etidocaine, beta-eucaine, euprocine, fenalcomin, formocaine, hexylcaine, hydroxytetracaine, isobutyl p-aminobenzoate, leucinocaine mesylate, levoxadrol, lidocaine, mepivacaine , meprylcaine, metabutoxycaine, methyl chloride, myrtecaine, naepaine, octacaine, orthocaine, oxethazain, parethoxycaine, phenacaine, phenol, piperocaine, piridocaine, pol idocanol, pramoxin, prilocaine, procaine, propanocaine, proparacaine, propipocaine, propoxycaine, pseudococaine, pyrrocaine, ropivacaine, salicylic alcohol, tetracaine, tolycaine, trimecaine, zolamine, or one of their salts. Preferably, the anesthetic agent may be lidocaine and / or mepivacaine, and more preferably lidocaine hydrochloride.
    [0032] According to yet another particular embodiment, a method according to the present invention may further comprise a step g) of adding at least one additional active agent different from the compounds described above, this step g) being carried out previously, jointly and / or after crosslinking step b), preferably after step b). The choice and the amount of additional active ingredients are adjusted so as not to raise any risk of incompatibility with the other compounds used in a crosslinked gel according to the invention, and in particular with the polysaccharide and more particularly with hyaluronic acid. , and to be compatible with the uses considered.
    [0033] These adjustments are within the general skill of those skilled in the art. Among the additional active agents that may be used in the present invention, mention may be made of antioxidants, amino acids, vitamins, minerals, nucleic acids, coenzymes, adrenaline derivatives and their mixture, said additional compounds considered being distinct from those indicated above. According to yet another particular embodiment, a method of the invention can be carried out at least in part within a specific receptacle with a deformable wall, such as for example within a pocket, in particular that defined in FIG. FR 2 945 293. The crosslinked gel obtained at the end of the process of the invention as described above may not be directly injectable, particularly with regard to its excessively high concentration of polysaccharide and / or the possible presence of bi-or multi-functional epoxy crosslinking agent residues, or its physiological conditions and / or pH incompatible with use in the fields of applications considered above.
    [0034] In addition, the gel obtained at the end of the process of the invention may in particular have a rigidity that is too high to be injected as is in a patient. Consequently, several additional steps, known to those skilled in the art, may be implemented to obtain an injectable hydrogel. More particularly, a step of neutralizing and diluting this gel may be required to impart its implant qualities. These steps make it possible to reduce the crosslinked gel to a concentration of physiologically acceptable salts and pH. The chains of the polysaccharide network are then stretched, hydrated, while the pH is brought back to a value close to neutrality. These steps are clearly within the general skills of those skilled in the art. For still improved purity, especially to remove residues of crosslinking agent (s) not attached to (x) polysaccharide (s), at least one purification step can also be performed. Advantageously, this purification step can be carried out by one or more dialysis baths.
    [0035] Ultimately, the hydrogel thus obtained can be filled in syringes under controlled atmosphere conditions, said syringes then being able to undergo a sterilization step, preferably thermally.
    [0036] Throughout the description, including the claims, the phrase "having one" should be understood as being synonymous with "having at least one", unless the opposite is specified. Expressions "between ... and ..." and "ranging from ..." must be understood as inclusive terms, unless otherwise specified.
    [0037] The following examples are presented by way of illustration and not limitation of the invention. For each of the following examples, unless indicated otherwise, the% expressed are% by mass.
    [0038] PROTOCOLS 1) Procedure for preparing a crosslinked gel of hyaluronic acid The procedure for preparing all the gels described in the examples below is as follows: a) 10 g of NaHA are introduced into an aqueous solution of 1% sodium hydroxide, so as to obtain a homogeneous final solution (ie at the end of step c) below) at 12% NaHA, b) The crosslinking solution (= BDDE diluted 20% in aqueous solution of 1% sodium hydroxide, where appropriate in the presence of a compound A, the nature and amount of which are specified in each of the examples) is added to the mixture of step a). The incorporated amount of this solution is adjusted according to the desired molar ratios RBDDE = nBDDE / nHA, and RA = nA / nHA, as indicated in each of the examples. c) The mixture thus formed (ie obtained at the end of step b)) is homogenized until total dissolution of the HA (ie until the absence of agglomerate and obtaining a color d) The homogeneous mixture obtained at the end of step c) is crosslinked according to the conditions described in each of the examples. e) After crosslinking reaction, the material obtained is neutralized by addition of HC1 and diluted in a solution of phosphate buffered saline pH 7.3, so as to obtain a hydrogel at the desired concentration of HA (= [HA] in mg / g, as specified in each of the examples), 5 f) L The hydrogel obtained is then purified by dialysis, according to the knowledge of the person skilled in the art. g) According to the examples, a non-crosslinked HA solution is optionally incorporated and homogenized with the purified hydrogel of cross-linked HA obtained at room temperature. the result of step f) (expressed in% HA uncrosslinked / HA uncrosslinked + crosslinked, such as pre in each of the 10 examples), and h) The hydrogel is then introduced into syringes which are then sterilized by autoclave (moist heat) at T °> 121 ° C, so as to obtain a FO> 15 (sterilizing value). 2) Viscoelastic properties of the tested gels (ie elastic modulus G ', phase shift angle 8, compressive strength, injection force and resistance to degradation) The viscoelastic properties of the gels are characterized in oscillatory rheology with strain sweep, by measuring their elastic modulus G '(in Pa) and their phase shift angle θ (°), measured at 1 Hz for a stress of 5 Pa. More precisely, these measurements are made at 25 ° C. at a frequency of 1 Hz, with strain sweep using a Thermo Haake RS6000 rheometer with 1 ° / 35mm diameter cone-plane geometry. G 'and δ are read at an applied deformation stress of 5 Pa, i.e. in the viscoelasticity domain where G' and δ remain stable (i.e. in the linear viscoelasticity range ). The elastic modulus G ', or conservation module, measures the energy restored by the gel when it is subjected to a small deformation. This magnitude can be imaged by the stiffness of a spring.
    [0039] The phase-shift angle 8 characterizes the degree of viscoelasticity of a material: it varies between 0 ° for a 100% elastic material (all the deformation energy is restored by the material, i.e. it returns to its original shape) and 90 ° for a 100% viscous material (all the deformation energy is lost by the material, that is to say that it flows and totally loses its initial shape) . A skin filling gel must be predominantly elastic to ensure its filling properties, that is to say that b must be <45 °. The compressive strength, which corresponds to the average strength of a gel when compressed between 2 trays, is also measured. This quantity is measured at 25 ° C, with 2.5 g of gel placed between 2 circular trays of 35 mm diameter, with an initial air gap of 10 mm. A compression of 70% of the gap height is applied at a speed of 0.1 mm / s. The compressive strength is the integration over time of the resistance force of the gel, it is therefore expressed in Ns. Finally, the injection force of the gels is measured in a syringe (long lmL format) with 27G1 needles. / 2 thin-walled, using a compression bench at the descent speed of 12.5mm / min. The resistance to degradation is evaluated by the loss of elastic modulus G ': between before and after sterilization: this loss represents a degradation at heat; and after sterilization, by degradation by incubation with H 2 O 2: this loss represents a degradation at oxidative stress (addition of 67 μl of 10% H 2 O 2 solution in 2 g of gel followed by homogenization of the medium and then incubation for 24 h at 37 ° C). The G 'is measured before degradation and after incubation for 24 h at 37 ° C in the presence of the H 2 O 2 solution. G 'is measured according to the aforementioned protocol. This G 'resulting from the difference observed between two different moments, it is expressed in percentage (%).
    [0040] EXAMPLES Example 1: Effect of a Phosphate Salt (STMP) Three cross-linked hyaluronic acid gels lb, lc and ld, cross-linked in the presence of different concentrations of sodium trimetaphosphate (STMP) as Compound A, are prepared according to the aforementioned procedure. The gel is devoid of STMP and is therefore the witness. It is also prepared according to the aforementioned procedure. Table 1 below details the nature and amounts of the compounds used.
    [0041] Table 1 Parameters RA RBDDE Cross-Linkage [HA] (mg / g) HA ttot (in hours and in ° C) HA t-nt-recovered [4 la (comparative) 0 lb (invention 0.03 72 H at 21 ± 2 ° C 0.02 23 10% lc (invention) 0.06 (BDDE + STMP) ld (invention) 0.09 The viscoelastic properties of the gels 1a, 1b, 1c and 1d, measured according to the above protocols are presented in Table 2 below. Table 2 G '(in Pa) 8 (in.) Compressive strength (in Ns) Injection force (in N) la (comparative) 14 50.9 3.1 10.3 lb (invention) 36 37.9 6 , 12.5 lc (invention) 49 33.9 10.3 14.0 ld (invention) 54 31.8 14.8 14.8 3029928 21 The gel (control) is not conducive to filling wrinkles, since its phase shift angle b is greater than 45 °. In other words, the amount of crosslinking agent used is too small to obtain a crosslinked gel satisfactory in terms of filling wrinkles.
    [0042] On the other hand, the gels lb, lc and ld according to the present invention, although manufactured with the same amount of BDDE, have an angle b of less than 45 ° and are therefore satisfactory in terms of wrinkle filling. This effect is related to the presence of STMP in the crosslinking system. Moreover, it is observed that the more the amount of STMP increases, the more the elasticity of the gel 10 increases (i.e. decrease of δ), and the more the elastic modulus increases. The increase in the amount of STMP between the gels lb, lc and ld according to the invention is also accompanied by an increase in the compressive strength, thus revealing more and more consistent and deformation-resistant gels. The degradation resistance properties of the 1a, 1b, 1c and 1d gels, measured according to the abovementioned protocols, are presented in Table 3 below. Table 3 Loss of G 'after sterilization (%) Loss of G' after oxidative stress (%) (comparative) 43 89 lb (invention) 14 65 lc (invention) 9 65 ld (invention) 19 48 Rate of change Gels la and ld are then evaluated in terms of the rate of change of hyaluronic acid. For this purpose, gels Ia and Id gels are washed / precipitated with isopropanol. The solids obtained are dried and then solubilized in D20, and treated in the presence of hyaluronidase (type VI-S, Sigma, 3kU) in 1 ml of D20 for degradation of the gel, in order to obtain a liquid matrix for analysis. Each homogeneous mixture obtained is then analyzed in 1 H NMR.
    [0043] Measurement rate of the modification rate The characterization of the modification rate is carried out by NMR spectroscopy. The degree of modification is obtained by applying the method developed by L. Nord et al. on HA samples cross-linked to BDDE. The degree of modification is achieved by integrating the 1H NMR signal of the N-acetyl group (8.2ppm) present in the HAs and a signal present in the crosslinking agent (two -CH2- groups, 51.6ppm). The ratio of the integrals of these two signals (crosslinking agent / NAc HA) corresponds to the degree of modification, after correction of the number of protons bound to each signal. Integral 8H1.6 4 Integral 81-12.0 3 MoD = The NMR analysis is carried out on Bruker Avance spectrometer 1 operating at 400 MHz ('H).
    [0044] The degrees of modification measured according to the above protocol for the gels 1a and 1d are presented in the table below. GEL Degree of modification la (comparative) 1.4% ld (invention) 1.4% The same type of NMR analysis, but carried out in Phosphorus NMR (NMR 3113) was carried out. As such, the primary reference in NMR 3113 is phosphoric acid 58% aqueous (8 = 0 ppm). This NMR analysis was performed on a Bruker 25 Avance 1 spectrometer operating at 400 MHz (H) and 161.97 MHz (3113).
    [0045] This analysis did not show a clash between hyaluronic acid and a phosphorylated species derived from STMP. The use of STMP in the presence of the BDDE for carrying out the crosslinking reaction thus makes it possible to obtain crosslinked gels with satisfactory filling properties (mechanical properties and resistance to degradation), although such properties are not achievable at the molar ratio (nBDDE / nHA) considered. Moreover, this effect of STMP is without increasing the rate of modification of hyaluronic acid (HA).
    [0046] Example 2: Confirmation of the effect of a phosphate salt (STMP) on more crosslinked gels (ie rBDDE greater than that of Example 1) Three crosslinked hyaluronic acid gels 3b, 3c and 3d comprising the use of different concentrations of STMP as Compound A, are prepared according to the above-mentioned procedure.
    [0047] The gel 3a is devoid of STMP and is therefore the control. It is also prepared according to the aforementioned procedure. Table 4 below details the nature and amounts of the compounds used. Table 4 Parameters RA RBDDE Crosslinking [HA] (in mg / g) H Ano :, meets IIA nar recu CL, L e-retLcut4 3a (comparative) 0 3b (invention) 0.02 72 H at 21 ± 2 ° C 0 , 04 18 10% 3c (invention) 0.04 (BDDE + STMP) 3d (invention) 0.06 3029928 24 The viscoelastic properties of the gels 3a, 3b, 3c and 3d, measured according to the abovementioned protocols, are presented in the table 5 below. Table 5 G '(in Pa) 8 (in.) Compressive strength (in Ns) Injection force (in N) 3a (comparative) 96 16.2 16.4 12.4 3b (invention) 107 15.3 17 11.3 3c (invention) 117 14.0 18.0 10.8 3d (invention) 197 10.8 20.2 9.5 Despite a lower HA concentration than that used in Example 1, the gel 3a has satisfactory properties for a function of filling wrinkles, with a phase shift angle b of less than 45 ° and much higher mechanical properties. This increase in mechanical properties is related to the amount of BDDE used (RBDDE = 0.04) greater than that of Example 1. The amount of BDDE crosslinking agent used in this gel 3a is therefore satisfactory to obtain an effective gel on the plane of filling the wrinkles. The gels 3b, 3c and 3d according to the present invention have mechanical properties superior to those of the control gel 3a. This effect is related to the presence of STMP in association with the BDDE. As the amount of STMP increases, an increase in mechanical properties is important. Thus, the 3d gel has an elastic modulus G 'more than 2 times that of the control gel 3a. The compressive strength also increases with the amount of STMP used. Finally, it is interesting to note that the injection force tends to decrease with the gels 3b, 3c and 3d according to the present invention; the injection force is in all cases lower than that obtained in Example 1, thanks to the use of a lower HA concentration. The improvement of the mechanical properties of a crosslinked gel 3029928 25 according to a method according to the invention is therefore not at the expense of the injection force for a customary degree of crosslinking. The properties of resistance to degradation of gels 3a, 3b, 3c and 3d, measured according to the abovementioned protocols, are presented in Table 6 below.
    [0048] Table 6 Loss of G 'after sterilization (%) Loss of G' after oxidative stress (%) 3a (comparative) 40 73 3b (invention) 3c (invention) 18 45 3d (invention) 3b gels, 3c and 3d crosslinked in the presence of STMP show a resistance to degradation much higher than that of crosslinked gel 3a without STMP. 3d gel is the most resistant, with a relative loss of elastic modulus G 'minimum.
    [0049] Example 3 Effect of Different Phosphate Salts Unlike sodium trimetaphosphate (STMP) which is cyclic, sodium triphosphate (STPP) is a linear phosphate salt. STMP and STPP are both triphosphate, the quantity tested is therefore RA = 0.06, for comparison with 3d gel of Example 2, identical but with STMP.
    [0050] Unlike STMP and STPP which are triphosphates, sodium phosphate (SP) is a monophosphate. The quantity tested is always RA = 0.06 for the gel 4c. Thus, three cross-linked hyaluronic acid gels 3d, 4b and 4c comprising the use of sodium trimetaphosphate (STMP), sodium triphosphate (STPP) or sodium phosphate (SP) as compound A, are prepared according to the above-mentioned procedure. .
    [0051] The gel 3a, devoid of phosphate salt is therefore the control. It is also prepared according to the aforementioned procedure. The gels 3a and 3d are those of Example 2. Table 7 below details the nature and amounts of the compounds used.
    [0052] Table 7 Parameters A RA RBDDE Cross-linking MAY (mg / g) H At t: C11 reagented HA. , r = eculé - étLeef. 3a (comparative) / 0 0.04 72H at 21 ± 2 ° C 18 10% (BDDE + STMP) 3d (invention) STMP 0.06 4b (invention) STPP 0.06 4c (invention) SP 0.06 Properties viscoelastic gels 3a, 3d, 4b and 4c measured according to the protocols mentioned above, are presented in Table 8 below. Table 8 G '(Pa) 8 (0) Compressive strength Injection force (in Ns) (in N) 3a (comparative) 96 16.2 16.4 12.4 3d (invention) 197 10.8 20.2 9.5 4b (invention) 123 12.0 16.8 10.6 4c (invention) 106 16.4 16.6 9.3 The mechanical properties of the gels 4b and 4c remain better than those of the control gel 3a without salt of phosphate. STPP and SP therefore also have a beneficial effect on viscoelastic properties. The degradation resistance properties of gels 3a, 3d, 4b and 4c, measured according to the abovementioned protocols, are presented in Table 9 below.
    [0053] Table 9 Loss of G 'after sterilization (%) Loss of G' after oxidative stress (%) 3a (comparative) 40 73 3d (invention) 4b (invention) 16 29 4c (invention) 31 62 As for the 3d gel crosslinked in the presence of STMP, the resistance to degradation is improved for the crosslinked gels 4b in the presence of STPP, and for the gel 4c crosslinked in the presence of SP.
    [0054] The use of STPP or SP in the presence of the BDDE in the crosslinking medium also makes it possible to obtain an advantageous effect on the mechanical properties. Resistance to degradation is also improved with the use of these STPP and SP phosphate salts.
    [0055] Example 4: Demonstration of a synergistic effect of a phosphate salt (STMP) used during cross-linking with BDDE Four crosslinked hyaluronic acid gels 5a, 51), 5c and 5d comprising the use of BDDE and STMP at As a compound A, are prepared according to the aforementioned procedure.
    [0056] The gel 5a is in accordance with the present invention because obtained after a crosslinking step in the simultaneous presence of BDDE and STMP. The gels 51), 5c and 5d are not in accordance with the present invention because they are obtained after a dissociated crosslinking step. Indeed, the BDDE and the STMP were integrated sequentially and with a significant time interval with regard to the crosslinking.
    [0057] Table 10 below details the nature and amounts of the compounds used.
    [0058] Table 10 RA RBDDE parameters Cross-linking at 21 ± 2 ° C [IIAI, HA no, ,, kicut. mg / g HA ,,,,,, -.-, c, -1 ,,. - neither. 5a (invention) 0.06 0.04 72H STMP + BDDE 18 0 5b (comparative) 72H STMP then 72H BDDE 5c (comparative) 24H STMP then 72H BDDE 5d (comparative) 72H BDDE then STMP added post-crosslinking The viscoelastic properties of the gels 5a , 5b, 5c and 5d measured according to the abovementioned protocols, are presented in Table 11 below. Table 11 G '(Pa) δ (°) Compressive strength (Ns) Injection force (N) 5a (invention) 136 9.6 22.6 38.0 5b (comparative) 17 18.5 3.2 11, 5c (comparative) 87 13.5 17.7 31.8 5d (comparative) 76 13.7 17.8 34.9 The gel 5a according to the invention exhibits the optimum rheological properties, thanks to crosslinking carried out at BDDE in the presence of STMP. If the same amount of STMP is incorporated after crosslinking with BDDE, the effect on the mechanical properties is no longer observed: thus the gel 5d has significantly lower mechanical properties.
    [0059] Also, there is no improvement in the mechanical properties of the gel if the STMP is incorporated in the HA 24H before the addition of the BDDE (gel 5c), and there is even degradation of the mechanical properties of the gel if the STMP is added 72H before the addition of the BDDE (gel 5b). In other words, these results demonstrate that the effect of the {STMP + BDDE} reaction is not equivalent to {STMP} + {BDDE}; therefore, there is a synergistic effect when the crosslinking reaction of the HA is carried out by an undissociated combination of BDDE and STMP. EXAMPLE 5 Effect of STMP with Faster Crosslinking Conditions Three crosslinked hyaluronic acid gels 6a, 6b and 6c comprising use of BDDE alone (ie 6a) or with STMP as Compound A (ie, 6b and 6b). 6c) are prepared according to the above-mentioned procedure. Table 12 below details the nature and amounts of the compounds used.
    [0060] Table 12 RA RBDDE Ratios IRAI cross-linking, non-cross-linked HA mg / gr - cross-linked HA + haem. Cross-linked 6a (comparative) 0 3H at 52 ± 2 ° C 6b (invention) 0.06 0.15 (BDDE + 20 10 % STMP) 6c (invention) 0.15 This mode of heat crosslinking (52 ° C) is interesting in that it is faster than at room temperature. The viscoelastic properties of the gels 6a, 6b and 6c measured according to the above-mentioned protocols are presented in Tables 13 below.
    [0061] Table 13 G '(Pa) δ (°) Compressive Strength (Ns) Injection Force (N) 6a (Comparative) 217 10.5 18.1 10.1 6b (Invention) 299 10.2 19.0 11.1 6c (invention) 426 9.5 18.9 10.2 Again, an increase in the elastic modulus G 'is observed when the crosslinking is carried out in the presence of the phosphate salt (STMP).
    权利要求:
    Claims (21)
    [0001]
    REVENDICATIONS1. A process for the preparation of a crosslinked gel of at least one polysaccharide or a salt thereof, comprising at least the steps of: a) providing a solution of an aqueous medium comprising at least said polysaccharide (s) or one of its salts in a non-crosslinked form, at least one bi- or multi-functional epoxide crosslinking agent and at least one phosphate salt; b) crosslinking the solution of step a) and, if appropriate; e) recovering said crosslinked gel formed.
    [0002]
    2. Method according to the preceding claim, characterized in that it further comprises at least one step d) of homogenizing the solution of step a), this step being performed previously and / or simultaneously to the step of crosslinking b), preferably prior to the crosslinking step b).
    [0003]
    3. Method according to claim 1 or 2, characterized in that the crosslinking step b) is carried out at a temperature below 35 ° C, preferably at a temperature ranging from 15 to 25 ° C, and better still from 19 to 23 ° C.
    [0004]
    4. Method according to the preceding claim, characterized in that the b) crosslinking step is carried out for a period of between 5 hours and 336 hours, preferably between 20 hours and 150 hours, and preferably between 40 hours and 100 hours.
    [0005]
    5. Process according to any one of the preceding claims, characterized in that the phosphate salt is chosen from sodium salts, potassium salts, lithium salts, cesium salts, silver salts, and mixtures thereof, preferably a sodium salt.
    [0006]
    6. Method according to any one of the preceding claims, characterized in that the phosphate salt is selected from sodium phosphate, sodium triphosphate, sodium trimetaphosphate, and mixtures thereof, preferably sodium trimetaphosphate.
    [0007]
    7. Process according to any one of the preceding claims, characterized in that the bi- or multi-functional epoxy crosslinking agent is / are chosen from butanediol diglycidyl ether, diepoxy-octane or 1,2-diol. bis- (2,3-epoxypropyl) -2,3-ethylene, and mixtures thereof, preferably butanediol diglycidyl ether. 3029928 32
    [0008]
    8. Process according to any one of the preceding claims, characterized in that the polysaccharide is liyaluronic acid or one of its salts, preferably sodium hyaluronate.
    [0009]
    9. Process according to any one of the preceding claims, characterized in that the hyaluronic acid salt is chosen from the sodium salt, the potassium salt, the zinc salt and the silver salt, and mixtures thereof. preferably the sodium salt.
    [0010]
    10. Process according to any one of the preceding claims, characterized in that the solution of step a) comprises a molar ratio "number of moles of phosphate salt (s) / total number of moles of polysaccharide units" included between 0.005 and 1, preferably between 0.01 and 0.25.
    [0011]
    11. Process according to any one of the preceding claims, characterized in that the solution of step a) comprises a molar ratio "total number of moles of polysaccharide units / number of moles of epoxy crosslinking agent (s) bi - or multi-functional "between 0.005 and 1, preferably between 0.01 and 0.25.
    [0012]
    12. Method according to any one of the preceding claims, characterized in that said method further comprises a step e) of adding at least one non-crosslinked polysaccharide, preferably uncrosslinked hyaluronic acid, this step e) being performed previously, jointly or after the recovery step c), but necessarily after step b).
    [0013]
    13. Method according to any one of the preceding claims, characterized in that the (s) crosslinked polysaccharide (s) included in the crosslinked gel has (s) a modification rate of less than 10%, preferably between 0.1% and 5%, and more preferably between 0.4% and 2.5%, or even between 0.7% and 1.6%.
    [0014]
    14. Method according to any one of the preceding claims, characterized in that the crosslinked gel has an elastic modulus (G ') of between 20 and 1000 Pa, preferably between 35 Pa and 400 Pa, associated with a phase shift angle ( O) less than 45 °.
    [0015]
    15. Injectable and sterile dermatological composition comprising, in a physiologically acceptable medium, at least one crosslinked gel obtained by carrying out a process as defined according to any one of claims 1 to 14.
    [0016]
    16. Cosmetic or dermatological composition comprising at least one crosslinked gel obtained by carrying out a process as defined according to any one of Claims 1 to 14.
    [0017]
    17. Kit comprising: a package containing at least one dose of a crosslinked gel obtained by carrying out a process as defined according to any one of claims 1 to 14 or a composition as defined claim 14 or 15; and an injection device in or through the skin or a device for micro-perforating the skin; dedicated to the administration of said dose.
    [0018]
    18. Crosslinked gel obtained by carrying out a process as defined according to any one of claims 1 to. 14, for its use for filling the volume defects of the skin, and in particular the filling of wrinkles.
    [0019]
    19. Crosslinked gel obtained by carrying out a method as defined in any one of claims 1 to 14, for its use for the treatment of gingival deficiencies, in particular periodontal diseases and associated disorders.
    [0020]
    20. Crosslinked gel obtained by carrying out a process as defined in any one of claims 1 to 14 for its use for articular viscosupplementation.
    [0021]
    21. Crosslinked gel obtained by carrying out a process as defined according to any one of claims 1 to 14, for its use for the treatment of ophthalmic disorders, in particular for cataract extraction, insertion and removal of intraocular lenses (IOL).
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    RU2640911C2|2012-06-15|2018-01-12|Мерц Фарма Гмбх Унд Ко. Кгаа|Method for obtaining of composition based on hyaluronic acid|
    ES2661913T3|2013-05-08|2018-04-04|Allergan Industrie|Hyaluronic acid gels crosslinked with sodium trimetaphosphate|US20190269582A1|2016-11-03|2019-09-05|Merz Pharma Gmbh & Co. Kgaa|Method for preparing hyaluronic acid dermal fillers, dermal fillers obtained thereby and their use|
    EP3354258A1|2017-01-31|2018-08-01|Teoxane SA|Use of a cohesive gel as a matrix material in a periodontal pocket|
    KR20200066248A|2018-11-30|2020-06-09|주식회사 엘지화학|Composition for synovial fluid substitute comprising hyaluronic acid|
    CN109762183A|2019-01-02|2019-05-17|华熙生物科技股份有限公司|A kind of preparation method and products thereof of sodium trimetaphosphate cross-linked hyaluronic acid gel|
    法律状态:
    2015-10-30| PLFP| Fee payment|Year of fee payment: 2 |
    2016-06-17| PLSC| Publication of the preliminary search report|Effective date: 20160617 |
    2016-11-30| PLFP| Fee payment|Year of fee payment: 3 |
    2017-10-30| PLFP| Fee payment|Year of fee payment: 4 |
    2018-10-30| PLFP| Fee payment|Year of fee payment: 5 |
    2019-12-20| PLFP| Fee payment|Year of fee payment: 6 |
    2020-11-26| PLFP| Fee payment|Year of fee payment: 7 |
    2021-09-27| PLFP| Fee payment|Year of fee payment: 8 |
    优先权:
    申请号 | 申请日 | 专利标题
    FR1462401|2014-12-15|
    FR1462401A|FR3029928B1|2014-12-15|2014-12-15|RETICULATED GEL|FR1462401A| FR3029928B1|2014-12-15|2014-12-15|RETICULATED GEL|
    US15/536,039| US10307512B2|2014-12-15|2015-12-15|Process for preparing hydrogels|
    PL15817187T| PL3233043T3|2014-12-15|2015-12-15|Process for preparing hydrogels|
    PT158171876T| PT3233043T|2014-12-15|2015-12-15|Process for preparing hydrogels|
    ES15817187T| ES2767307T3|2014-12-15|2015-12-15|Procedure for preparing hydrogels|
    PCT/EP2015/079889| WO2016096920A1|2014-12-15|2015-12-15|Process for preparing hydrogels|
    EP15817187.6A| EP3233043B1|2014-12-15|2015-12-15|Process for preparing hydrogels|
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