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  • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
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  • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
  • C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
  • C08B37/0027—2-Acetamido-2-deoxy-beta-glucans; Derivatives thereof
  • C08B37/003—Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
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  • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
  • A61K31/716—Glucans
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  • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
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  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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  • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
• • A—HUMAN NECESSITIES
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  • A61P39/06—Free radical scavengers or antioxidants
• • C—CHEMISTRY; METALLURGY
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  • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
  • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
  • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
  • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
  • C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
• • C—CHEMISTRY; METALLURGY
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  • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
  • C08J3/00—Processes of treating or compounding macromolecular substances
  • C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
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  • C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules
  • C08J3/246—Intercrosslinking of at least two polymers
• • C—CHEMISTRY; METALLURGY
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  • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
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  • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
  • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
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  • A61L2300/236—Glycosaminoglycans, e.g. heparin, hyaluronic acid, chondroitin
• • A—HUMAN NECESSITIES
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  • A61L2430/00—Materials or treatment for tissue regeneration
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• • A—HUMAN NECESSITIES
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  • A61L2430/00—Materials or treatment for tissue regeneration
  • A61L2430/06—Materials or treatment for tissue regeneration for cartilage reconstruction, e.g. meniscus
• • C—CHEMISTRY; METALLURGY
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  • C08J2305/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
• • C—CHEMISTRY; METALLURGY
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  • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
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  • C08J2405/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
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  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
  • C08L2201/00—Properties
  • C08L2201/08—Stabilised against heat, light or radiation or oxydation
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  • C08L2205/02—Polymer mixtures characterised by other features containing two or more polymers of the same C08L -group
  • C08L2205/025—Polymer mixtures characterised by other features containing two or more polymers of the same C08L -group containing two or more polymers of the same hierarchy C08L, and differing only in parameters such as density, comonomer content, molecular weight, structure

Definitions

• the present invention relates to a crosslinked carboxyalkyl chitosan, forming a matrix, compositions comprising it, its manufacturing process and its various applications, in particular in the therapeutic, rheumatological, ophthalmological, aesthetic medicine, plastic surgery, internal surgery, dermatology and gynecological fields. , or cosmetic.
• Chitosan derivatives are known, in particular in the applications from Kiomed Pharma published under the numbers WO 2016/016463 and WO 2016/016464 and the corresponding patents. It is also known from Kiomed Pharma advantageous chitosan derivatives such as carboxyalkyl chitosans described in the patent applications of Kiomed Pharma filed under the numbers PCT / EP2018 / 080763 and PCT / EP2018 / 080767 and their family whose contents are integrated into the present invention by reference.
• compositions and in particular the hydrogels of the state of the art one of the technical problems of the compositions based on biopolymers, known to those skilled in the art, lies in the fact that certain compositions are not present in form of cohesive hydrogel, that is, the hydrogel spontaneously disintegrates into distinct parts in the presence of an aqueous medium, thus forming particles, fragments. It is also called a gel or fragmented hydrogel.
• the chitosan is advantageously purified and then preferably dried.
• the process of the invention can comprise a stage of drying the carboxyalkyl chitosan, then optionally of grinding the latter to obtain a powder.
• the carboxyalkyl chitosan can be dried, for example by evaporation of water, for example by a spray-drying (atomization) or fluidized bed process, or by heat drying under vacuum or at atmospheric pressure, or alternatively by lyophilization.
• the carboxyalkyl chitosan can be solubilized in an aqueous solution, and for example in a water of pharmaceutical grade acceptable for injection or implantation in a body, and in particular a human body.
• the substituted chitosan preferably has an average molecular weight of 150,000 to 220,000 and a degree of substitution ranging from 50 to 200%, the molecular weight preferably being expressed before substitution.
• the substituted chitosan has a degree of substitution ranging from 50 to 200%, and preferably from 70 to 200%, and a degree of acetylation of 40 to 80%, and preferably from 50 to 75%.
• the substituted chitosan has a degree of substitution ranging from 90 to 200%, and preferably from 90 to 150%, and a degree of acetylation of 40 to 80%, the molecular mass preferably being expressed before substitution.
• the substituted chitosan has a degree of substitution ranging from 90 to 200%, and preferably from 90 to 150%, and a degree of acetylation of 40 to 60%, and preferably from 50 to 60%.
• the substituted chitosan preferably has an average molecular mass of 220,000 to 300,000, a degree of substitution ranging from 90 to 200%, and preferably from 90 to 150%, and a degree of acetylation of 50 to 75%, the molecular mass preferably being expressed before substitution.
• soluble in water is understood to mean that the carboxyalkyl chitosan exhibits no cloudiness visible to the naked eye when it is placed in aqueous solution. More specifically, it is possible to confirm the solubility, that is to say the absence of cloudiness, of a solution of carboxyalkyl chitosan at a concentration of for example 1% (w / w) in water or a buffer, for example a phosphate buffer, with an optical density of less than 0.5, and preferably less than 0.2, measured by UV-visible spectrometry at the wavelength of 500 nm with reference to a reference cell comprising only the aqueous solvent used for the sample being measured, but in the absence of the substituted chitosan.
• Another method consists of a visual inspection according to monograph 2.9.20 of the European Pharmacopoeia.
• the composition is not soluble in a satisfactory pH range, for example from pH 5.5 to pH 8.5, at room temperature.
• the carboxyalkyl chitosan is sterile.
• crosslinked by covalent bonds between the chains of carboxyalkyl chitosan is understood to mean in particular that the main chain of chitosan (also called backbone of chitosan or in English of “chitosan backbone”) is covalently linked to one or more main chains of chitosan. .
• a three-dimensional network of chitosan molecules is thus advantageously obtained.
• the invention is not limited to a particular covalent crosslinking method, but a method using a chemical molecule serving as a crosslinking agent, also called a crosslinking agent, is preferred.
• the crosslinks are formed by a crosslinking agent forming said covalent bonds.
• Genipin is a naturally occurring crosslinking agent used to crosslink polysaccharides, in particular carboxymethyl chitosan (Yang et al. Acta Pharmacol Sin 31, 1625, 2020). Genipin stains the hydrogel from a dark blue to black color, which may be of benefit in some indications.
• the crosslinking agent is a polyepoxide type agent, for example difunctional.
• BDDE 4-butanediol diglycidyl ether
• EGDE ethylene glycol diglycidyl ether
• the crosslinking agent is divinyl sulfone.
• the composition of the invention can also comprise a biopolymer other than the crosslinked carboxyalkyl chitosan.
• the biopolymer is a polysaccharide, oxidized or not, crosslinked by covalent bonds or not, for example a glycosaminoglycan, and in particular a hyaluronan such as for example hyaluronic acid or sodium hyaluronate.
• the matrix according to the invention comprises a crosslinked carboxyalkyl chitosan and a hyaluronan, a chondroitin sulfate and / or a carboxymethyl cellulose.
• a crosslinked carboxyalkyl chitosan hydrogel as defined for the invention
• a hyaluronan it is one of the objects of the invention to combine these two polymers in order to be able to combine, for example, the recognized moisturizing properties of hyaluronan with the protective properties against oxidative stress of chitosan.
• the matrices according to the invention comprise only crosslinked carboxymethyl chitosan or else a crosslinked carboxymethyl chitosan combined with a hyaluronan, crosslinked or not. This makes it possible to adapt the desired properties.
• the carboxyalkyl chitosan is crosslinked in an alkaline aqueous phase, for example in the presence of a sodium hydroxide (NaOH) solution.
• NaOH sodium hydroxide
• the reaction is carried out with heating, for example at a temperature of 25 to 60 ° C, and for example 50 ° C, for example over a period of 30 minutes to 48 hours, for example 1 hour to 5 hours .
• the crosslinking is stopped by neutralization and dilution, for example by adding an acid, and for example by adding acetic acid or a hydrochloric acid.
• the reaction residues are removed by dialysis using a phosphate buffered saline.
• a hydrogel comprising a matrix according to the invention.
• carboxyalkyl chitosan is an exogenous molecule that is more resistant to degradation than hyaluronan after implantation / injection / instillation into a body.
• the invention relates to a matrix comprising a three-dimensional network based on these two polymers of different molecular masses.
• the invention relates to a matrix comprising at least one hyaluronan co-crosslinked by covalent bonds with the carboxyalkyl chitosan.
• the process for preparing a matrix comprising a carboxyalkyl chitosan, preferably as defined according to the invention, co-crosslinked with another biopolymer, and preferably a hyaluronan, said process comprising:
• crosslinking of the carboxyalkyl chitosan and the other biopolymer, and preferably a hyaluronan, by the crosslinking agent
• a matrix according to the invention is sterile.
• the invention relates to a hydrogel, and advantageously forms a cohesive hydrogel.
• the present invention therefore relates to crosslinked carboxyalkyl chitosan hydrogels in which the carboxyalkyl chitosan has a high degree of acetylation (DA) (greater than 40%), and preferably also has a high degree of substitution (DS) (greater than 20). %, preferably greater than 50% and typically less than 200%).
• DA acetylation
• DS degree of substitution
• the invention relates to a composition comprising at least one matrix defined according to the invention.
• a matrix according to the invention is formulated in an aqueous medium to form a composition in the form of a hydrogel.
• the concentration of polymer is less than 10%, for example less than or equal to 5%, by mass relative to the total mass of the composition, and in particularly of the hydrogel (m / m).
• the concentration of polymer is less than 4%, for example less than or equal to 3%, by mass relative to the total mass of the composition, and in particular hydrogel (m / m).
• the mass ratio (m / m) [carboxyalkyl chitosan / hyaluronan] is for example from 5 to 95%, for example from 10 to 90%, and again for example from 30 to 70%.
• the mass ratio (m / m) [hyaluronan / carboxyalkyl chitosan] is for example from 5 to 95%, for example from 10 to 90%, and again for example from 30 to 70%.
• the mass ratio (m / m) [carboxyalkyl chitosan / hyaluronan] is 1/1 (ie 50% chitosan and 50% hyaluronan).
• the aqueous medium can be water, an aqueous solution, the pH and osmolality of which are for example adjusted using an acid / base buffer system with the addition of salts and / or optionally polyols (sorbitol, mannitol, glycerol).
• the matrix according to the invention is formulated in a hydrolipidic medium making it possible to form an emulsion, single or multiple, direct or inverse.
• the osmolality of the composition of the matrix is between 250 and 400 mosm / kg, and preferably from 270 to 330 mosm / kg.
• the composition of the matrix has an osmolality suitable for a joint.
• the composition of the matrix has an osmolality compatible with an ocular or intraocular surface.
• the composition of the matrix has an osmolality compatible with the dermis or the mucous membranes.
• the osmolality of the composition of the matrix is between 100 and 400, and more specifically between 120 and 380 mosm / kg.
• composition according to the invention is sterile.
• the composition according to the invention is contained in an injection, implantation or instillation device such as for example a syringe or a vial.
• the injection device such as for example a syringe
• steam sterilization can then be packaged, preferably aseptically or sterile. It can also be a bag, a flap, or a flask allowing instillation of the composition according to the invention, filled aseptically after sterilization of the formulation, or directly sterilized after filling.
• a composition according to the invention is sterilized by filtration and / or by steam sterilization, before filling an injection, implantation or implantation device. instillation, such as a syringe or a vial.
• the invention also relates to a pharmaceutical composition
• a pharmaceutical composition comprising at least one matrix, preferably in the form of a hydrogel, according to the invention.
• the composition according to the invention is used as an injectable pharmaceutical composition, implantable or suitable for instillation, or an injectable or implantable medical device or suitable for instillation.
• the invention also covers a composition according to the invention in a dry form, in particular in a lyophilized form.
• a composition according to the invention in a dry form, in particular in a lyophilized form.
• the present invention relates more particularly to a composition according to the invention for use for a therapeutic treatment, for example comprising the injection by the subcutaneous, intradermal, intraocular, or intraarticular, intramucosal, intramuscular route of the said injection.
• composition for example for repairing, regenerating or filling at least one body tissue / fluid in need of repair or filling.
• biomechanical properties sought by the composition according to the invention can vary in nature and in amplitude according to the indication, for example according to the tissue in which hydrogel is to be incorporated, the mechanism of action or effect intended to ensure the benefit to the patient, and the duration of the effect.
• the properties of the composition according to the invention and in particular of a hydrogel according to the invention are suited to the indication.
• the final polymer concentration (carboxyalkyl chitosan and / or other biopolymers such as a hyaluronan), and / or the degree of crosslinking, in particular via the mass ratio of the crosslinking agent / polymers, and / or the nature and / or quantity of ions, and / or initial molecular mass of the polymer (s).
• the invention relates to a very elastic hydrogel, in particular when it is necessary to ensure a lasting increase in volume at the cutaneous, subcutaneous or periosteal level (for projection or remodeling), or a viscoelastic gel, in particular to allow both the shock absorption and a lubricating effect on the joints.
• the invention relates to a lubricating hydrogel, in particular when it is necessary to reduce the friction between two biological surfaces, for example two surfaces of cartilage in a joint, or the ocular surface and the eyelids in an eye.
• a composition of the invention can exhibit a variable level of elasticity, adjusted according to the indication, and which can be characterized by measuring the modulus of elasticity by rheometry.
• the matrix has an antioxidant capacity by capturing free radicals, in particular a standardized antioxidant capacity greater than 0.30, preferably greater than 0.50, and more preferably greater than 0.80, and for example greater than 0 , 90.
• the present invention relates to an injectable composition characterized in that it comprises at least one matrix defined according to the invention.
• the present invention relates to a pharmaceutical composition characterized in that it comprises at least one matrix defined according to the invention.
• the composition according to the invention is used as an injectable pharmaceutical composition, implantable or suitable for instillation, or topical administration, or an injectable or implantable medical device or suitable for instillation, or administration.
• topical for example for use in a method of therapeutic treatment, for example comprising instillation or topical administration or injection by the subcutaneous, intradermal, mucosal, ocular, intraocular, or intra-articular, intra- bone, of said composition, for example for repairing or filling in at least one body tissue requiring repair or filling.
• the composition according to the invention is used in a method for the treatment, repair or filling of at least one liquid or body tissue requiring repair or filling, and for example the body tissue of which is chosen from tissues belonging to the vocal cords, muscles, ligaments, tendons, mucous membranes, sexual organs, bones, joints, eyes, dermis, or any of their combinations, and more particularly the dermis, the cartilage, the synovial membrane, a skin wound or even the ocular surface.
• the present invention relates to a composition according to the invention for its use in a method of treating arthritis, or repairing a cartilage defect, for example by injection into a biological fluid, for example synovial fluid, or after admixture with a biological fluid, eg blood, and implantation in cartilage.
• biological fluid is meant a fluid of bodily origin which may or may not have undergone a treatment modifying its composition.
• the present invention relates to a medical device, for example a medical implant, characterized in that it comprises or consists of a composition as defined according to the invention.
• the present invention relates in particular to a composition according to the invention for use for a therapeutic, surgical or cosmetic treatment, including in particular a treatment in rheumatology, in ophthalmology, in gynecology, in aesthetic medicine, in plastic surgery, in surgery. internal, orthopedic and gynecological surgery, for the prevention of post-surgical tissue adhesions, in dermatology.
• the present invention also relates to a composition according to the invention for use for a therapeutic treatment of dry eye syndrome, corneal injury or eye or joint inflammation.
• the present invention further relates to the application of a composition according to the invention by instillation on the ocular surface to prevent or combat a corneal lesion, or dry eye syndrome, in particular with the aim of lubricating or regenerating. the ocular surface.
• the invention also relates to a composition of eye drops comprising a carboxyalkyl chitosan defined according to the present invention.
• the subject is affected by an inflammatory pathology (e.g. osteoarthrosis, arthritis, dry eye syndrome).
• an inflammatory pathology e.g. osteoarthrosis, arthritis, dry eye syndrome.
• the present invention relates more particularly to a composition according to the invention for the treatment of osteoarthritis, arthritis, or the repair of a cartilage defect, for example by injection into the synovial cavity or by implantation at the level of the defect. of cartilage.
• the present invention relates more particularly to a medical device, for example a medical implant, characterized in that it comprises or consists of a composition according to the invention.
• composition according to the present invention can also comprise one or more active agents for a desired indication, and / or one or more additives or excipients making it possible to modulate the properties of the composition according to the invention.
• the present invention also relates to a composition according to the invention for use in a method of therapeutic treatment.
• the present invention also relates to a composition according to the invention for its use in a method of treating osteoarthritis, or repairing a cartilage defect, for example by injection into the synovial pocket or after mixing with blood and implantation. in the cartilage / bone.
• composition according to the invention is formulated in a solid form (for example a film or a porous foam), which swells / hydrates once implanted (eg: tear plug, bandage).
• a solid form for example a film or a porous foam
• the composition is formulated in the form of a nebulizable composition (spray).
• the present invention also relates to a composition according to the invention for use in a method of treatment or aesthetic care of one or more tissues or organs affected by excessive temperature, as in the case of a burn.
• the present invention also relates to a composition according to the invention for use in a method of treating cartilage repair (for example by implantation on a cartilage defect in order to promote its regeneration).
• the invention relates to a physiological composition, administered topically, by injection or by implantation, intended to come into contact with one or more living tissues subjected to oxidative stress, for example:
• intra-articular injection for the treatment of osteoarthrosis via supplementation of synovial fluid, lubrication of cartilage, absorption of shock at the articular level, regeneration of the synovial membrane); intra-articular implantation to promote repair of cartilage defects; - intraosseous implantation to promote bone repair (osteoinduction / osteoconduction);
• “easy” injection is preferably meant that the force to be exerted on such a syringe to eject into the air is less than 30 Newton (at a speed of 10 mm / min) to cause a composition according to the invention to flow through it.
• a 27 gauge needle preferably a force of less than 20 Newton.
• the ranges of osmolality and pH values of the composition are suitable, and generally close to the osmolality and pH values of the tissues in contact with the composition according to the invention.
• translucent we mean that we can distinguish an object by placing its composition between the eye of the observer and the object.
• transparent is meant that one can distinguish alphanumeric characters when placing the composition between the eye of the observer and the observed characters. In general, this evaluation is carried out with a composition thickness of about 1 cm.
• the method of monograph 2.9.20 of the European Pharmacopoeia can also be followed for visual inspection. It is also possible to measure the optical density of the composition, for example by UV-visible spectrometry at 500nm and ensure that the optical density is less than 0.5, preferably 0.2 relative to a reference solvent.
• the present invention also covers the use of a composition according to the invention for the preparation of a pharmaceutical composition, in particular for a therapeutic treatment, for example as defined more specifically by the invention.
• the solubility range is established by preparing a solution of the polymer to be tested at a concentration of 1% and a pH of 9, by dividing it into several fractions, the pH of which is adjusted to different pH over a range of 9 to 1.
• the polymer is verified for each fraction to be soluble, that is to say that it does not form a cloudiness, according to the visual inspection method of monograph 2.9.20 of the European Pharmacopoeia.
• the pH range over which the polymer is soluble or insoluble is noted.
• the biomechanical profile of the sample is characterized using a DHR- 2 Hydrid Rheometer (TA Instrument) equipped with a 20 mm planar geometry spaced at 700 ⁇ m with the peltier, at a temperature of 37 ° C, a frequency of 3.98 rad / s and an amplitude of deformation ranging from 0.1 to 10%.
• TA Instrument Hydrid Rheometer
• Each measurement is made in triplicate, then the average value of the moduli of elasticity (G ’), viscosity (G”) and tan d (G7G ’) of the three measurements is calculated.
• Two discs based on a polyacrylate type biomaterial used for the manufacture of hydrophobic intraocular lenses are hydrated beforehand by immersion in water at 60 ° C for approximately 2 hours, then fixed on the upper and lower geometries of a DHR-2 rheometer (TA Instruments)
• a volume of approximately 100mI_ of the test sample is placed on the lower disc, then the upper geometry is lowered to contact between the two discs, up to an imposed normal force of 5 Newtons
• the friction coefficient measurements are carried out at 25 ° C for a period of 150 seconds, at constant normal force (5N), oscillation frequency of 1 , 256 rad / s and deformation angle of approximately 0.05 radians, according to a protocol adapted from the protocol described by Waller et al.
• Two discs based on a polyacrylate type biomaterial used for the manufacture of hydrophobic intraocular lenses are hydrated beforehand by immersion in water at 60 ° C for approximately 2 hours, then fixed on the upper and lower geometries of a DHR-2 rheometer (TA Instruments)
• a volume of approximately 100 pL of the test sample is placed on the lower disc, then the upper geometry is lowered to contact between the two discs, up to an imposed normal force of 5 Newtons
• the friction coefficient measurements are carried out at 25 ° C for a period of 150 seconds, at constant normal force (5N), oscillation frequency of 1 , 256 rad / s and deformation angle of approximately 0.05 radians, according to a protocol adapted from the protocol described by Waller et al.
• the measurement is carried out using a MultiTest 2.5-i compression bench (Mecmesin) equipped with a 100N compression cell. A suitable needle is fitted to the syringe that contains the sample. Position the syringe on the bench, press the syringe plunger at a constant speed (for example 10 or 80mm / min), then measure the force required for ejection. The maximum force tolerated by the equipment is approximately 70 Newtons.
• the in vitro 'ABTS' test is applied. This test consists in determining the capacity of a substance to trap the radical cation of 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS * 1), a chromophore whose maximum absorption is at the wavelength 734 nm in its radical cation form.
• ABTS * 1 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid)
• ABTS * 1 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid)
• a positive control is used in order to express the antioxidant capacity in a standardized way from one series to another, ascorbic acid (vitamin C) in solution at the concentration of 0.02 mg / ml (20pg / ml) .
• the TEAC is first measured for ascorbic acid solutions of 0.005 to 0.05 mg / mL. The absorbance of the 0.02 mg / ml ascorbic acid solution is verified to be within the linearity zone.
• the standardized antioxidant capacity of the product tested is expressed by the TEAC (product) / TEAC (ascorbic acid at 0.02 mg / mL) ratio.
• Step 1 carboxymethylation of chitosan.
• CC1 to CC6 are carboxymethyl chitosans derived from chitosan of fungal origin, and prepared according to the above method.
• CC7 is a commercial carboxymethyl chitosan derived from crustaceans, supplied by the company Kraeber (product code 5313009900, Ellerbek, Germany).
• a measured by solid phase carbon-13 NMR (formula 2); b: measured by potentiometric titration; c: measured by capillary viscometry; d: the signal of the acetyl group is not detectable by carbon 13 NMR (weak DA).
• a crosslinked matrix is prepared starting from the carboxymethyl chitosan CC3 after adjusting the reaction parameters (Table 2a, reference M1 -A).
• CC3 has a degree of acetylation of 55% and a degree of carboxymethylation of 87%, measured by carbon 13 NMR (formula 2).
• the hydrogel formed by the matrix is transferred into 3mL glass syringes which are sterilized by steam via a short cycle, in a SYSTEC-DX-65 autoclave (condition "A2").
• the final polymer concentration of the sterilized hydrogel obtained (M1 -A) is determined by mass balance.
• the probe 2'-7'-dichloro-dihydrofluorescein diacetate which becomes fluorescent under the effect of free radicals, is added for 30 minutes.
• the culture of each well is then rinsed with HBSS to remove the product to be tested, the cells are replaced in the HBSS, then all the wells are irradiated with UVA at 12.5J / cm 2 for 20 minutes to generate ROS.
• This hydrogel is compared with those of two commercial products based on uncrosslinked HA intended for treating the ocular surface (references B7 and B8, Table 8b). Their lubrication capacity is measured in the same series of tests as that of M8-B.
• the two hydrogels of crosslinked CC and co-crosslinked CC / HA exhibit a modulus of elasticity G 'in the same range as that of B9, while B10 has a higher modulus of elasticity. It is observed that the two hydrogels of CC and CC / HA exhibit a significant lubricating capacity, characterized by a low coefficient of friction between the two surfaces, is comparable to that of the viscosupplement of crosslinked HA B10, and better than that of the viscosupplement of crosslinked HA B1 1.
• Example 11 - HA co-crosslinking test with a CC with a degree of acetylation less than 40%

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