Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/14—Macromolecular materials
  • A61L27/26—Mixtures of macromolecular compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
  • A61K31/738—Cross-linked polysaccharides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
  • A61K8/04—Dispersions; Emulsions
  • A61K8/042—Gels
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
  • A61K8/73—Polysaccharides
  • A61K8/731—Cellulose; Quaternized cellulose derivatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
  • A61K8/73—Polysaccharides
  • A61K8/733—Alginic acid; Salts thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
  • A61K8/73—Polysaccharides
  • A61K8/735—Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
  • A61K8/73—Polysaccharides
  • A61K8/736—Chitin; Chitosan; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
  • A61L27/52—Hydrogels or hydrocolloids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
  • A61L27/58—Materials at least partially resorbable by the body
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/16—Emollients or protectives, e.g. against radiation
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
  • A61Q19/08—Anti-ageing preparations
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
  • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
  • A61K2800/59—Mixtures
  • A61K2800/594—Mixtures of polymers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
  • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
  • A61K2800/91—Injection
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2400/00—Materials characterised by their function or physical properties
  • A61L2400/06—Flowable or injectable implant compositions

Definitions

• the invention relates to the field of crosslinked biodegradable hydrogels having esthetic applications, for example, or medicinal applications.
• periurethral injection for the treatment of urinary incontinence by sphincter insufficiency
• postsurgical injection for preventing peritoneal adhesions in particular
• injection for replacement of deficient biological fluids in the joints in particular for replacing deficient synovial fluid
• injection subsequent to surgery for far-sightedness by scleral incisions with a laser for example, of periurethral injection for the treatment of urinary incontinence by sphincter insufficiency, postsurgical injection for preventing peritoneal adhesions in particular, injection for replacement of deficient biological fluids (in the joints in particular for replacing deficient synovial fluid) and injection subsequent to surgery for far-sightedness by scleral incisions with a laser.
• the hydrogels used have to exhibit optimized properties in terms of persistence in vivo, of rheology and of viscosity in order to guarantee good “injectability”, these hydrogels being applied by injection using needles of variable sizes depending on the applications but which have to remain as fine as possible in order to minimize postinjection reactions.
• compositions based on permanent or very slowly biodegradable particles dispersed in an injection vector for example PMMA (polymethyl methacrylate) particles in a collagen gel (Artecoll), acrylic hydrogel particles in a crosslinked sodium hyaluronate gel (Dermalive, Dermadeep) or polylactic acid or polylactide (PLA) particles in an aqueous vector (New Fill, Sculptra, the PLA being resorbed in 1 to 4 years depending on the size of the particles).
• PMMA polymethyl methacrylate particles in a collagen gel
• Acrylic hydrogel particles in a crosslinked sodium hyaluronate gel Dermadeep
• PLA polylactic acid or polylactide
• biodegradable implants based on crosslinked or noncrosslinked polysaccharides essentially based on sodium hyaluronate.
• IPN interpenetrating polymer networks
• Si-IPN semi-interpenetrating polymer networks
• Patent application FR 2 733 427 describes compositions which comprise a continuous phase and a dispersed phase composed of insoluble fragments of a hydrogel.
• the aqueous continuous phase acts as vehicle for the injection of the fragments of the dispersed phase.
• the present invention makes it possible to solve these various disadvantages.
• the present invention consists of a biodegradable single-phase cohesive hydrogel, characterized in that it is composed of a homogeneous mixture of x identical or different polymers, crosslinked prior to their interpenetration by mixing, in the single-phase hydrogel form, said crosslinked polymers being insoluble in water and miscible with one another and x being between 2 and 5.
• cohesiveness and the single-phase nature of a gel according to the invention is understood to mean the property of said gel of retaining its stability and its unity without the possibility of separation of the constituent gels.
• mixing is understood to mean a juxtaposition of x polymers without creation of a covalent bond between them. Interactions take place between the various polymers due to the presence of polar groups and of the aqueous medium; these interactions are of the low energy weak bond type involving forces such as, for example, intermolecular hydrogen bridges, indeed even ionic bonds.
• the mixture thus obtained exhibits properties comparable to those of IPNs without being an IPN within the meaning of the IUPAC definition; this is because this definition excludes mixtures of networks crosslinked beforehand. In this instance, however, the cohesive and crosslinked beforehand gels are intimately mixed, generating weak interchain bonds between them.
• Such a product exhibits the advantages of IPN networks without the disadvantages of employing the latter and makes it possible, by virtue of the use of a different degree of crosslinking for each constituent gel (or an identical degree of crosslinking, if the gels have very different molecular weights), to create more or less dense networks before their final hydration and, after mixing, to obtain a product having rheological properties which can be “adjusted” by measuring the properties of the various constituent gels before the mixing.
• crosslinking reactions can thus be carried out on isolated polymers, thus avoiding the problems of selectivity.
• crosslinking conditions are simple, each gel being crosslinked independently of one another.
• the synergy is obtained as a result of the optimization of the two parameters which act mutually on one another, low crosslinking being favorable to the injectability and unfavorable to the persistence and high crosslinking being favorable to the persistence and, a contrario, unfavorable to the injectability.
• the respective properties of the networks complement one another; thus the gel with the highest elastic parameter will bring about an increase in the elastic parameter of the combination, in comparison with the least crosslinked gel.
• the gel with the lowest level of injectability will make it possible to reduce the level of injectability of the combination.
• the characteristics of the final mixture are thus optimized, with a synergy of the elastic and viscous parameters of the mixtures obtained, which can be modified according to the respective proportions of each of the constituent gels and the pathology targeted.
• the persistence of the gel will be known and predictable, apart from the factors of inter-individual variation, and the reproducibility of the injectability properties will make possible great control of the action and the elimination of a number of side effects.
• a hydrogel because of its makeup, will exhibit decomposition kinetics which depend on the number of gels mixed and on the degrees of crosslinking. This is because the decomposition kinetics depend on several parameters: the degree of crosslinking, the concentration of polymer and the molecular weights of the polymers used at the time of crosslinking.
• the decomposition kinetics will be slowed down: this is because to homogeneously mix gels with variable degrees of persistence will make it possible to strengthen the overall persistence by an effect of “diluting” the random cleavages of the gel via either free radicals or enzymes (hyaluronidases, and the like) present in the dermis or the biological fluid replaced.
• the finished product thus manufactured will thus be more persistent for equivalent levels of injectability, while remaining perfectly biodegradable.
• the persistence will also be optimized as a result of the interpenetration of the networks, increasing the density of crosslinks or chemical bonds while retaining the mechanical and chemical independence of the 2 to x crosslinked gels.
• random attack of the free radicals is statistically lower in comparison with a simple single-phase gel (just 1 network, faster weakening of the bonds at the surface, lower density of chemical bonds).
• Accessibility to the core of the gel will also be rendered much more difficult for decomposition by enzymes or via CD44 antigens.
• the use of different molecular weights in each single-phase gel crosslinked beforehand will make it possible to form networks with a more or less dense structure or meshwork and thus to further strengthen the persistence in vivo.
• the hydrogel according to the invention is characterized in that the polymers are selected from polysaccharides.
• the hydrogel according to the invention is characterized in that the polymers are selected from the group consisting of polylactic acids and their derivatives, N-vinylpyrrolidone, polyvinyl acids, polyacrylamides and acrylic polymers and biologically acceptable derivatives.
• the polysaccharides are selected from the group consisting of hyaluronic acid, keratan, heparin, cellulose and cellulose derivatives, alginic acid, xanthan, carrageenan, chitosan, chondroitin and their biologically acceptable salts.
• At least one of the x polysaccharides is selected from the group consisting of hyaluronic acid and its biologically acceptable salts.
• the hydrogel according to the invention is characterized in that at least one of the x polysaccharides is selected from the group consisting of cellulose derivatives and their biologically acceptable salts.
• the hydrogel according to the invention is characterized in that at least one the x polysaccharides is selected from the group consisting of chondroitin and its biologically acceptable salts.
• the hydrogel according to the invention is characterized in that at least one of the x polysaccharides is selected from the group consisting of chitosan and its biologically acceptable salts and derivatives.
• polysaccharides which can be employed in the hydrogel according to the present invention are of any type known in the field and are preferably selected from those produced by bacterial fermentation.
• the polysaccharides which can be used in the context of the present invention exhibit a molecular weight MW of between approximately 0.02 and approximately 6 MDa, preferably of between approximately 0.04 and approximately 4 MDa and more preferably of between approximately 0.05 and approximately 3 MDa.
• hyaluronic acid and its salts especially its salts acceptable from the physiological viewpoint, such as the sodium, potassium or calcium salts, advantageously the sodium salt.
• chondroitin sulfate and its salts and cellulose derivatives such as hydroxypropylmethylcellulose or carboxymethylcellulose, and the mixtures of two or more of them.
• the constituent gels of the hydrogel according to the invention are preferably based on sodium hyaluronate.
• the x polymers are identical.
• the x polymers are different.
• the hydrogel according to the invention is characterized in that x is equal to 2.
• the first of the x polysaccharides is selected from the group consisting of hyaluronic acid and its salts, cellulose derivatives and their salts and xanthan and the second is selected from the group consisting of chondroitin sulfate and its salts, chitosan and its salts and derivatives, cellulose derivatives and their salts and alginic acids.
• the first of the x polymers is selected from the group consisting of hyaluronic acid and its salts, cellulose derivatives and their salts and xanthan and the second is selected from the group consisting of polylactic acids and their derivatives and acrylic derivatives.
• the first of the x polymers is selected from the group of sodium hyaluronate and the second is selected from the group consisting of chondroitin sulfate and its salts, chitosan and its salts and derivatives, cellulose derivatives and their salts and alginic acids.
• the ratio by weight of the highly crosslinked polysaccharide to the weakly crosslinked polysaccharide can vary within very wide proportions, according to the nature of the polysaccharides used, their respective degrees of crosslinking and also the final properties targeted.
• the proportion by weight of the highly crosslinked polysaccharide gel in the finished product is between approximately 0.1 and 99.9%, preferably from 5 to 50%, of gel 1 exhibiting a degree of crosslinking x1 and from 50 to 95% of gel 2 exhibiting a degree of crosslinking x2 or even more preferably from 10 to 40% of gel 1 exhibiting a degree of crosslinking x1 and from 60 to 90% of gel 2 exhibiting a degree of crosslinking x2.
• the invention also relates to the process for the preparation of a biodegradable hydrogel according to the invention; this process comprises a stage of developing specifications which fix the rheological properties targeted as a function of the applications.
• an elasticity is targeted, that resulting from the degree of crosslinking, and, for the determination of the injectability, the viscosity at a high shear rate, also related to the degree of crosslinking, is set; these parameters depend on the starting materials, in particular on their molecular weight.
• the process for the preparation of a biodegradable single-phase cohesive hydrogel according to the invention is characterized in that it comprises at least the stages of:
• the hydration is carried out, for example, by immersion in or addition of a buffered isotonic solution.
• the process additionally comprises x stages of crosslinking x polymers before mixing the x crosslinked polymers.
• the hydration is generally carried out in an aqueous medium by simple mixing of the mixture of crosslinked gels with an aqueous solution, advantageously a buffered physiological aqueous solution, so as to obtain a final concentration which can vary within very wide proportions according to the nature of the polysaccharides used, their respective degrees of crosslinking and also the use envisaged.
• the buffered solution which can be used can, for example, be an osmolar physiological solution exhibiting a pH of between approximately 6.8 and approximately 7.5.
• This final concentration of total polysaccharides is generally between approximately 5 and approximately 100 mg/g, preferably between approximately 5 and approximately 50 mg/g, for example approximately 20 mg/g, of hydrogel.
• the process of the present invention thus makes it possible to obtain a biodegradable single-phase cohesive hydrogel which can be injected and with a long lasting persistence.
• the two crosslinking stages are carried out in a medium having a pH value which is identical or different.
• Each of these stages can be carried out in an acidic or basic medium, preferably in a basic medium, for example at a pH of between 8 and 14, preferably between 8 and 13.
• crosslinking reactions employed in the process of the invention are reactions well known to a person skilled in the art.
• a person skilled in the art can develop and optimize the crosslinking conditions according to said polysaccharide and said crosslinking agent: degree of crosslinking, temperature, pH.
• degree of crosslinking degree of crosslinking
• temperature degree of crosslinking
• pH pH
• the crosslinking agents which are involved in the crosslinking stages are generally bi- or polyfunctional crosslinking agents of various types and can, for example, be selected from DVS (divinyl sulfone) in an alkaline medium (see U.S. Pat. No. 4,582,865), bi- or polyfunctional epoxy compounds (see U.S. Pat. No. 4,716,154), carbodiimides, or formaldehyde (see GB 2 151 244).
• BDDE 1,4-butanediol diglycidyl ether
• diepoxyoctane 1,2-bis(2,3-epoxypropyl)-2,3-ethylene.
• Preference is very particularly given to the use of 1,4-butanediol diglycidyl ether (BDDE) for each of the crosslinking stages.
• each of the crosslinking stages can be carried out with one or more crosslinking agents, it being possible for the latter to be identical or different in one or another of the stages, under the pH conditions indicated above.
• the polysaccharides can advantageously be purified according to conventional purification techniques (for example by washing with a continuous stream of water, dialysis baths, and others), in order to remove the unreacted residual crosslinking agent.
• crosslinking stages can advantageously be followed by a neutralization stage (i.e., neutralization as far as a pH value of approximately 7), for example by addition of an appropriate amount of 1N hydrochloric acid.
• a neutralization stage i.e., neutralization as far as a pH value of approximately 7
• the x polymers exhibit different degrees of crosslinking, at least one of the x polymers exhibiting a degree of crosslinking x1 and at least one of the x polymers exhibiting a degree of crosslinking x2, and x1 being greater than x2.
• the x polymers exhibit identical degrees of crosslinking, it being understood that the polymers can have different molecular weights.
• x1 and x2 are between 0.02 and 0.4 and preferably between 0.08 and 0.2.
• crosslinking it may be advantageous to neutralize the gel obtained according to standard processes known in the field, for example by addition of acid, when the crosslinking is carried out in a basic medium, and by addition of a base, when the crosslinking is carried out in an acidic medium.
• the mixture obtained on conclusion of the process can optionally be subjected to an additional hydration stage, in order to obtain a gel in the form of an injectable hydrogel suitable for the applications envisaged.
• the invention relates to the use of a hydrogel according to the invention in the formulation of a viscosupplementation composition.
• the invention relates to the use of a hydrogel according to the invention in the formulation of a composition for filling in wrinkles.
• the applications targeted are more particularly the applications commonly observed in the context of injectable polysaccharide viscoelastic products used or which can potentially be used in the following pathologies or treatments:
• the hydrogel according to the invention can be used:
• the hydrogel according to the invention also has an important application in joint surgery and in dental surgery for filling in periodontal pockets, for example.
• the hydrogel according to the invention can also have an entirely advantageous application as matrix for releasing one (or more) active principle(s) dispersed beforehand within it.
• active principle is understood to mean any product which is active pharmacologically: medicinal active principle, antioxidant active principle (sorbitol, mannitol, and the like), antiseptic active principle, anti-inflammatory active principle, local anesthetic active principle (lidocaine, and the like), and the like.
• the hydrogel according to the invention preferably after purification and hydration to give the hydrogel, can be packaged, for example in syringes, and sterilized according to any means known per se (for example by autoclaving) in order to be sold and/or used directly.
• the present invention relates to a kit comprising a hydrogel according to the invention packaged in a sterile syringe.
• x number of moles of crosslinking agent introduced into the reaction medium/total number of disaccharide units introduced into the reaction medium.
• Sodium hyaluronate fibers of injectable grade (1 g: molecular weight: approximately 2.7 MDa) are weighed out in a container.
• a 1% aqueous solution of sodium hydroxide in water (7.4 g) is added and the combined mixture is homogenized for approximately 1 hour using a spatula at ambient temperature and 900 mm Hg.
• BDDE noncrosslinked sodium hyaluronate
• NaHA noncrosslinked sodium hyaluronate
• the combined mixture is subsequently placed on a water bath at 50° C. for 2 h 20 in order to obtain a degree of crosslinking x1 of approximately 0.14.
• the crosslinked final gel is subsequently neutralized by addition of 1N HCl and placed in a phosphate buffer bath in order to stabilize the pH and to make possible its hydration or swelling as far as 30 mg/g of HA.
• An NaHa hydrogel crosslinked by the route conventionally used is thus obtained: G1 with an HA concentration of approximately 30 mg/g.
• a portion of the gel is stored at this concentration and the other portion is diluted by addition of phosphate buffer in order to obtain, at the end, 20 mg/g of HA.
• This gel is subsequently homogenized before being filled into syringes which are sterilized by autoclaving: sterile syringes comprising gel G1 at 20 mg/g.
• Sodium hyaluronate fibers of injectable grade (1 g; molecular weight: approximately 1.5 MDa) are weighed out and dried beforehand in a container.
• BDDE 43 mg
• NaHA noncrosslinked sodium hyaluronate
• the crosslinked final gel is subsequently neutralized by addition of 1N HCl and placed in a phosphate buffer bath in order to stabilize the pH and to make possible its hydration or swelling as far as 30 mg/g of HA.
• An NaHa hydrogel crosslinked by the route conventionally used is thus obtained: G2 with an HA concentration of approximately 30 mg/g.
• the mixture thus obtained is a homogeneous gel comprising 20 mg/g of HA and composed of 2 inter-penetrating networks; this gel is then packaged into syringes and autoclaved.
• the mixture thus obtained is a homogeneous gel comprising 20 mg/g of HA and composed of 2 inter-penetrating networks; this gel is then packaged into syringes and autoclaved.
• the half-lives of the interpenetrating networks of gels obtained according to the invention are longer, guaranteeing a greater time of in vivo persistence.
• the product of “two-phase” type shows, after centrifuging, separated particles at the bottom of the syringe. If the product is ejected from the syringe, the viscous product exits first, followed by the particles, which have no cohesiveness with one another, agglomerated at the bottom of the syringe, and which render the injectability particularly difficult.
• IPN-Like Gel 1 70% Gel 1 cross. x1+30% Gel 2 cross. x2
• IPN-Like Gel 2 50% Gel 1 cross. x1+50% Gel 2 cross. x2
• IPN-Like Gel 3 30% Gel 1 cross. x1+70% Gel 2 cross. x2
• the extrusion force is characterized on a Mecmesin tensile/compression testing machine under a rate of compression of 50 mm/min with 23G1 1 ⁇ 4 needles; the results are given in the table below.
• the elasticity is characterized on a TA Instruments AR2000 Ex rheometer in oscillation at 25° C., the value of the elasticity being recorded at a frequency of 1 Hz; the results are given in the table below.
• This stage is identical to stage a) of the synthesis of Gel 1 of example 1.
• This stage is identical to stage b) of the synthesis of Gel 1 of example 1, with 81 mg of BDDE.
• a Gel 3 with a degree of crosslinking x3 of approximately 0.17 is obtained.
• This stage is identical to stage c) of the synthesis of Gel 1 of example 1, in order to obtain a gel G3 with an HA concentration of approximately 30 mg/g.
• a portion of the gel is stored at this concentration and the other portion is diluted by addition of phosphate buffer in order to finally obtain 24 mg/g of HA; this gel is subsequently homogenized before being filled into syringes which are sterilized by autoclaving: sterile syringes comprising gel G3 at 24 mg/g.
• the mixture thus obtained is a homogeneous gel comprising 24 mg/g of HA and composed of 2 inter-penetrating networks; this gel is then packaged into syringes and autoclaved.
• stage c) of example 1 Identical to stage c) of example 1 with 41 mg of BDDE.
• the combined product is brought to 50° C. on a water bath for 3 hours, in order to obtain a degree of crosslinking x6 of approximately 0.09.
• Gel G7 composed of the interpenetration of the 3 crosslinked gels (G4, G5 and G6), has the lowest extrusion force, for an elasticity value greater by approximately 20% than that of the gel G6 with a close but slightly greater level of injectability.
• BDDE 37 mg is added to the noncrosslinked CMC gel obtained in the preceding stage, the combined mixture being homogenized with a spatula for approximately 30 minutes at ambient temperature. The combined mixture is subsequently placed on a water bath at 50° C. for 3 h in order to obtain a degree of crosslinking x8 of approximately 0.19.
• the crosslinked final gel is subsequently neutralized by addition of 1N HCl and placed in a phosphate buffer bath in order to stabilize the pH and to make possible its hydration or swelling as far as 45 mg/g of CMC.
• An NaCMC hydrogel crosslinked by the route conventionally used is thus obtained: G8 with a CMC concentration of approximately 45 mg/g.
• the HA gel G1 crosslinked to a level of 0.14, at a concentration of 30 mg/g, is added in various proportions to the crosslinked NaCMC gel G8, the phosphate buffer is added in order to adjust the final concentrations to 26 mg/g of HA and 37 mg/g of CMC and the 2 gels are placed under slow mechanical stirring with the phosphate buffer for 1 hour under hyperbaric pressure.
• 3 interpenetrating gels as described below are thus obtained:
• interpenetrating gels are subsequently packaged into syringes and characterized by rheology (elastic modulus G′) and by injectability under a rate of 13 mm/min with 27G1/2 needles.
• the gels G1 and G8 are also adjusted to the concentrations of 26 mg/g for G1 and 37 mg/g for G8 in order to compare them with the 3 interpenetrating gels.
• G1 G8 G9 G10 G11 cross- (cross- Interpene- Interpene- Interpene- Interpene- linked HA, linked CMC, trating gel trating gel trating gel 26 mg/g) 37 mg/g) 30% G1 + 70% G8 50% G1 + 50% G8 70% G1 + 30% G8 Elastic modulus 235 265 240 243 264 G′ at 1 Hz

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