EP4329713A1 - Produit biocompatible a matrice comprenant un polysaccharide et du chitosane co-reticules - Google Patents

Produit biocompatible a matrice comprenant un polysaccharide et du chitosane co-reticules

Info

Publication number
EP4329713A1
EP4329713A1 EP22719360.4A EP22719360A EP4329713A1 EP 4329713 A1 EP4329713 A1 EP 4329713A1 EP 22719360 A EP22719360 A EP 22719360A EP 4329713 A1 EP4329713 A1 EP 4329713A1
Authority
EP
European Patent Office
Prior art keywords
matrix
chitosan
salt
composition
hyaluronic acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP22719360.4A
Other languages
German (de)
English (en)
French (fr)
Inventor
Alexandre ADAMCZEWSKI
Gautier LALEVEE
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Falgagen
Noxelis
Original Assignee
Falgagen
Noxelis
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Falgagen, Noxelis filed Critical Falgagen
Publication of EP4329713A1 publication Critical patent/EP4329713A1/fr
Pending legal-status Critical Current

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Classifications

    • 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
    • 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
    • A61K31/716—Glucans
    • A61K31/717—Celluloses
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    • 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
    • A61K31/716—Glucans
    • A61K31/722—Chitin, chitosan
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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
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
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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
    • A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate
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    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
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    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
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    • A61K9/0012—Galenical forms characterised by the site of application
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    • A61K9/08—Solutions
    • 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
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/446—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with other specific inorganic fillers other than those covered by A61L27/443 or A61L27/46
    • 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
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    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • 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
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • 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
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    • 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
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/06—Materials or treatment for tissue regeneration for cartilage reconstruction, e.g. meniscus
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/34—Materials or treatment for tissue regeneration for soft tissue reconstruction

Definitions

  • the present invention relates to the field of biocompatible products for cosmetic and/or medical, in particular surgical, purposes. It relates most particularly to a biocompatible product with a matrix comprising a polysaccharide at least partly co-crosslinked with chitosan, preferably a chitosan derivative or a chitosan salt.
  • viscoelastic products are also known which are used during ophthalmic surgeries in order to replace or supplement the aqueous humor (during cataract surgery or in the context of refractive surgery) or the vitreous humor ( in the case of a vitrectomy), as described in document US 4,716,154.
  • a certain number of biocompatible products in particular products comprising cross-linked hyaluronic acid or a salt of cross-linked hyaluronic acid, have made it possible to fill, replace, increase the volume of a biological tissue and/or replace, supplement a biological fluid.
  • some of them cannot be used effectively either in the cosmetic field or in the medical field because of their undesirable side effects and/or low efficacy.
  • Products based on cross-linked hyaluronic acid or cross-linked hyaluronic acid salt have a relatively satisfactory viscosity after cross-linking.
  • the viscosity of these products tends to decrease sharply after the completion of a heat treatment.
  • these products must be sterilized before their use in a human or animal, and this sterilization is generally carried out by heat treatment (for example by means of an autoclave).
  • Document US 10,898,613 B2 describes a biocompatible injectable hydrogel composition of cross-linked hyaluronic acid containing from 0.05 mM to 4 mM of zinc divalent cation to confer improved stability (evaluated by a viscosity parameter) after sterilization by autoclave.
  • Document FR 3 096260 A1 describes a co-crosslinking of carboxymethyl chitosan with hyaluronan with the aim of combining the recognized moisturizing properties of hyaluronan with the protective properties against oxidative stress of chitosan.
  • a problem proposed by the present invention is to provide a biocompatible product making it possible to better fill, replace, increase the volume of a biological tissue and/or replace, supplement a biological fluid.
  • the invention aims to provide such a product having improved rheological properties, in particular in terms of viscosity after application of a heat treatment such as sterilization by autoclave.
  • the invention provides a biocompatible product according to claim 1.
  • biocompatible product within the meaning of the present invention, is meant any product which is well tolerated by a living organism and which does not cause a rejection reaction, a toxic reaction, a lesion or a harmful effect on its biological functions.
  • chitosan derivative is intended to denote a substituted chitosan having a substitution of the D-glucosamine and/or N-acetyl-D-glucosamine units, and in which the substitution group is covalently bonded.
  • the Applicant has found that a co-crosslinking of a polysaccharide (chosen from the group comprising hyaluronic acid, a salt of hyaluronic acid, chondroitin sulphate, cellulose derivatives, and a mixture of these ci) with chitosan, a chitosan derivative or a chitosan salt, which leads to the establishment in the matrix of covalent bonds between the polysaccharide and the chitosan, chitosan derivative or chitosan salt, makes it possible to very significantly increase the viscosity of the product relative to the cross-linked polysaccharide.
  • a polysaccharide chosen from the group comprising hyaluronic acid, a salt of hyaluronic acid, chondroitin sulphate, cellulose derivatives, and a mixture of these ci
  • the divalent zinc cation can be introduced by adding a zinc saccharide to be crosslinked in the matrix.
  • crosslinked in the matrix within the meaning of the present invention, is understood to mean a bond to at least one of the constituents of the matrix by at least two covalent bonds.
  • the divalent zinc cation can be introduced by adding a zinc saccharide to be grafted into the matrix.
  • grafted into the matrix within the meaning of the present invention, means a bond to at least one of the constituents of the matrix by a covalent bond.
  • the divalent zinc cation can preferably be dispersed in the matrix.
  • the term "dispersed in the matrix” means an absence of covalent bond to the constituents of the matrix.
  • a dispersion in the matrix of the divalent zinc cation provided excellent results in terms of viscosity.
  • the manufacturing process is simpler than in the case of addition in view of a crosslinking or a graft, because zinc (in the form of a zinc salt or in the form of a zinc saccharide in particular) has a relatively poor solubility in the pH range necessary for a crosslinking or a graft.
  • the concentration of divalent zinc cation in the matrix can be between
  • the concentration of divalent zinc cation in the matrix can be less than or equal to 0.1% by weight relative to the total weight of the matrix.
  • the concentration of divalent zinc cation in the matrix can be between 0.002% and 0.06% by weight relative to the total weight of the matrix, and preferably between 0.01% and 0.6% by weight. weight relative to the total weight of the matrix.
  • concentration of divalent zinc cation in the matrix can be between 0.002% and 0.06% by weight relative to the total weight of the matrix, and preferably between 0.01% and 0.6% by weight. weight relative to the total weight of the matrix.
  • the divalent zinc cation can be included in the matrix by the addition of a zinc salt or a zinc saccharide, preferably zinc gluconate, zinc chloride or zinc sulphate.
  • Zinc gluconate helps to obtain a product with good transparency, in particular for applications requiring it (notably in the ophthalmological field or for injections close to the surface of the skin).
  • Zinc chloride and zinc sulphate have proved interesting for applications in rheumatology, in orthopedic surgery, or for the treatment of osteoarthritis or the repair of a cartilage defect.
  • the concentration of polysaccharide chosen from the group comprising hyaluronic acid, a salt of hyaluronic acid, chondroitin sulphate, cellulose derivatives, and a mixture thereof is between 0.01% and 3% by weight relative to the total weight of the matrix, and/or
  • the concentration of chitosan, chitosan derivative, or chitosan salt is between 0.01% and 3% by weight relative to the total weight of the matrix.
  • the chitosan derivative can be a carboxyalkyl chitosan.
  • carboxyalkyl chitosan Good results have in particular been obtained with carboxymethyl chitosan.
  • carboxya! ky! e chitosan is meant a chitosan having glucosamine units, N-acetyl-glucosamine units and glucosamine units substituted by a carboxyalkyl group. This is thus referred to as a chitosan derivative or a substituted chitosan.
  • the polysaccharide can be hyaluronic acid or a salt of hyaluronic acid, and can preferably have a molecular weight of between 0.1 and 5 MDa.
  • a cosmetic or pharmaceutical composition comprising a biocompatible product as previously described.
  • This cosmetic or pharmaceutical composition can be in the form of a viscoelastic solution or a hydrogel.
  • the cosmetic or pharmaceutical composition may comprise a physiologically acceptable buffer, preferably containing polyols (mannitol, sorbitol, glycerol) and/or phospholipids.
  • a physiologically acceptable buffer preferably containing polyols (mannitol, sorbitol, glycerol) and/or phospholipids.
  • said composition can be used in a method of cosmetic treatment or therapeutic treatment, comprising in particular topical application, implantation, instillation or injection by subcutaneous, intradermal, mucosal, ocular, intraocular, or intra-articular, of said composition.
  • said composition can be used for the prevention and/or treatment of pathologies which can be improved or avoided by:
  • said composition can be used for a method of treating osteoarthritis, or repairing a cartilage defect, the composition being for example formulated for administration by injection into the synovial fluid or for implantation in cartilage after mixing with blood, or for a method of treating dry eyes.
  • said composition can be used in a therapeutic, surgical or cosmetic treatment method, including in particular a treatment in rheumatology, ophthalmology, gynecology, aesthetic medicine, plastic surgery, internal surgery, in orthopedic surgery, for the prevention of post-surgical tissue adhesions, in dermatology.
  • the composition can be used in a therapeutic treatment of a dry eye syndrome, of a corneal lesion or of an ocular or articular inflammation.
  • said composition can be used in a therapeutic treatment during which said composition is applied by instillation on the ocular surface to prevent or fight against a corneal lesion or a dry eye syndrome, in particular with the aim of lubricate or regenerate the ocular surface.
  • an ophthalmic drop composition comprising a biocompatible product as previously described.
  • a method for manufacturing a biocompatible product as described above or a composition as described above comprising the following steps: a. dissolve in the same aqueous solution: i. a polysaccharide selected from the group comprising hyaluronic acid, a salt of hyaluronic acid, chondroitin sulphate, cellulosic derivatives, and a mixture thereof, preferably hyaluronic acid or a salt of hyaluronic acid , ii. chitosan, preferably a chitosan derivative, or a chitosan salt, b. adding a crosslinking agent to said aqueous solution and causing crosslinking of the mixture to form a matrix, c. add a divalent zinc cation before and/or after step b.
  • a polysaccharide selected from the group comprising hyaluronic acid, a salt of hyaluronic acid, chondroitin sulphate, cellulosic
  • the invention is not limited to a particular covalent crosslinking method, but a method using a chemical molecule serving as crosslinking agent, also called crosslinking agent, such as 1,4-butanediol diglycidyl ether (BDDE) or polyethylene glycol diglycidyl ether (PEGDE) in particular.
  • crosslinking agent such as 1,4-butanediol diglycidyl ether (BDDE) or polyethylene glycol diglycidyl ether (PEGDE) in particular.
  • this addition can be in the form of a zinc saccharide, with a view to crosslinking and/or grafting into the matrix, or can be in the form of a zinc salt which will be dispersed in the matrix.
  • step b When the divalent zinc cation is added after step b, this addition takes place in the form of zinc salt or zinc saccharide which is dispersed in the matrix.
  • the pH of the biocompatible product or of the composition can be adjusted between 6 and 8, preferably to 7.
  • the biocompatible product or the composition can be subjected to a heat treatment for sterilization, preferably a heat treatment at a temperature of between 120° C. and 140° C. for a period of between 1 and 20 minutes.
  • each example or embodiment has a general scope.
  • Figure 1 is a histogram of the viscosities of different formulations, measured before and after heat treatment.
  • Figure 2 is a graph illustrating the evolution of the viscosities of different formulations and different products on the market as a function of the shear rate.
  • CMCS carboxymethyl chitosan
  • PEGDE polyethylene glycol diglycidyl ether
  • a physiological buffer solution is prepared in deionized water to reach a pH of between 6 and 8 and an osmolality of between 250 and 350 mOsm/L.
  • hyaluronic acid or a salt of hyaluronic acid is designated by “HA”.
  • the crosslinking of the HA is carried out by dissolving the HA (for example sodium hyaluronate (NaHa)) in an aqueous solution of sodium hydroxide at 0.25 mol/L until complete solubilization.
  • a crosslinking agent for example BDDE or PEGDE
  • the crosslinking agent is then added and the mixture is mixed to homogenize.
  • the mixture is sealed and placed in a water bath at 50° C. for 3 hours to induce a crosslinking reaction of the HA. Covalent bonds are thus created between the crosslinking agent and the HA. Bridges can thus be formed between two HA chains.
  • the gel is then homogenized and neutralized in a container with the addition of an aqueous solution of hydrochloric acid to form a homogeneous and transparent phase. Dialysis is then performed to remove residual cross-linking agent and to stabilize pH and osmolarity.
  • a cross-linked phase comprising a polysaccharide (namely hyaluronic acid or a salt of hyaluronic acid) with chitosan.
  • a chitosan derivative or a chitosan salt To simplify the reader's understanding, hyaluronic acid or a salt of hyaluronic acid is designated by “HA”, while chitosan, a chitosan derivative or a salt of chitosan is designated by “CHITO”.
  • the crosslinking of HA with CHITO is carried out by dissolving the HA (for example sodium hyaluronate (NaHa)) and a "CHITO" (for example a carboxyalkyl chitosan) in an aqueous solution of soda at 0 .25 mol/L until complete solubilization.
  • a crosslinking agent for example BDDE or PEGDE
  • the crosslinking mixture is sealed and placed in a water bath at 50° C. for 3 hours to induce a simultaneous crosslinking reaction (or co-crosslinking) of the HA and of the CHITO.
  • silicates can be formed between two chains of HA, between two chains of CHITO, or between a chain of HA and a chain of CHITO.
  • the gel is then homogenized and neutralized in a container with the addition of an aqueous solution of hydrochloric acid to form a homogeneous and transparent phase. Dialysis is then performed to remove residual cross-linking agent and to stabilize pH and osmolarity.
  • hyaluronic acid or a salt of hyaluronic acid is designated by "HA”
  • chitosan, a derivative of chitosan or a salt of chitosan is designated by "CHITO”.
  • HA taken alone or with a CHITO, is dissolved in a physiological buffer solution until complete solubilization to form a transparent viscoelastic solution.
  • a divalent cation of zinc can be added by incorporating (by dispersion) into the solution a zinc salt or a zinc saccharide (in particular zinc gluconate, zinc chloride or zinc sulphate) .
  • a mixture dissolves and homogenizes the zinc salt in the linear phase.
  • Each formulation undergoes a heat treatment corresponding to a sterilization cycle.
  • This heat treatment is carried out in a laboratory autoclave HMT 260 MB from HMC EUROPE.
  • the 1-minute sterilization tray is set at a temperature of 131°C.
  • the total duration of the heat treatment including the rise in temperature, the plateau and the cooling is approximately 22 to 23 minutes.
  • the rheological characterizations are carried out using a Discovery "DHR2" hybrid rheometer from the company TA Instruments, equipped with a cone-plane geometry 40 mm in diameter and having an angle of 2 degrees, as well as a a truncation of 55 microns.
  • the rheometer is also equipped with a Peltier plate in order to control the temperature of the sample during the measurement.
  • the sample is placed on the lower plate and the geometry is lowered until it reaches the “trim gap” (105 ⁇ m). Excess product is removed with a spatula. Then the geometry went down to 55 ⁇ m from the lower plateau.
  • the method used consists of a flow ramp at 35° C. by applying a shear rate varying between 1 s" 1 and 1000 s" 1 , with 5 points per decade.
  • the viscosities for comparing the various formulations are then taken from the viscosity value corresponding to a shear rate of 8.6 s ⁇ 1 .
  • Test No. 1 Formulation of a biocompatible product with an HA cross-linked matrix, without divalent zinc cation present in the matrix
  • An HA formulation comprising an HA crosslinked phase is prepared.
  • the final concentration of HA is 0.9% by weight relative to the total weight of the matrix.
  • the crosslinked phase of HA is prepared as previously described.
  • the biocompatible cross-linked matrix product thus obtained has a density of approximately 1, and is then transferred into 1 mL glass syringes.
  • the glass syringes are then subjected to heat treatment as previously described, by autoclaving with a sterilization plate for 1 minute at 131°C.
  • the total duration of the heat treatment including the temperature rise, the plateau and the cooling is approximately 22 to 23 minutes.
  • Test N*2 Formulation of a biocompatible product with an HA cross-linked matrix, with a divalent zinc cation present in the matrix
  • An HA formulation comprising 90% crosslinked HA phase and 10% non-crosslinked (linear) phase based on HA is prepared.
  • the HA concentration is 0.9% by weight relative to the total weight of the matrix.
  • a divalent zinc cation is added by dispersion in the matrix.
  • the crosslinked phase of HA is prepared as previously described in connection with test No. 1.
  • NaHa sodium hyaluronate
  • the cross-linked phase and the linear (non-cross-linked) phase are then mixed in a 9:1 ratio.
  • a divalent zinc cation is added to the matrix by incorporating zinc gluconate into the solution (by means of a scatter).
  • a mixture makes it possible to dissolve and homogenize the zinc salt in the linear phase.
  • the biocompatible cross-linked matrix product obtained has a density of about 1, and is then transferred into 1 mL glass syringes.
  • the glass syringes are then subjected to heat treatment as described above, by autoclaving with a sterilization plate for 1 minute at 131°C.
  • the total duration of the heat treatment including heat-up, plateau and cool-down is approximately 22-23 minutes.
  • Test No. 3 Formulation of a biocompatible product with a co-crosslinked matrix HA and CHITO, without divalent zinc cation present in the matrix
  • a formulation of HA and of CHITO comprising 90% of HA-CHITO coreticulated phase is prepared.
  • concentrations of HA and CHITO are respectively 0.9% and 0.1% by weight relative to the total weight of the matrix.
  • the crosslinked phase of HA-CHITO is prepared as follows.
  • crosslinked and linear (non-crosslinked) phases are then mixed, respecting a 9:1 ratio.
  • the biocompatible cross-linked matrix product obtained has a density of approximately 1, and is then transferred into 1 mL glass syringes. [0101]
  • the glass syringes are then subjected to heat treatment as previously described, by autoclaving with a sterilization plate for 1 minute at 131°C.
  • the total duration of the heat treatment including the rise in temperature, the plateau and the cooling is approximately 22 to 23 minutes.
  • Test No. 4 Formulation of a biocompatible product with an oo-cross-linked HA and CHITO matrix, with a divalent zinc cation present in the matrix by adding zinc gluconate
  • a formulation of HA and of CHITO comprising 90% co-crosslinked HA-CHITO phase and 10% non-crosslinked (linear) phase based on HA-CHITO is prepared.
  • the concentrations of HA and CHITO are respectively 0.9% and 0.1% by weight relative to the total weight of the matrix.
  • the crosslinked phase of HA-CHITO is prepared as previously described in connection with test No. 3.
  • a linear phase with HA and CHITO is prepared as previously described in connection with test No. 3, except that after complete dissolution of sodium hyaluronate (NaHa) and carboxymethyl chitosan, a divalent zinc cation is added to the matrix by incorporating zinc gluconate into the solution (by means of a dispersion).
  • NaHa sodium hyaluronate
  • carboxymethyl chitosan carboxymethyl chitosan
  • crosslinked and linear (non-crosslinked) phases are then mixed, respecting a 9:1 ratio.
  • the biocompatible cross-linked matrix product thus obtained has a density of approximately 1, and is then transferred into 1 mL glass syringes.
  • the glass syringes are then subjected to heat treatment as described above, by autoclaving with a sterilization tray for 1 minute at 131°C.
  • the total duration of the heat treatment including the temperature rise, the plateau and the cooling is approximately 22 to 23 minutes.
  • Test No. 5 Formulation of a biocompatible product with a co-crosslinked matrix HA and CHITO, with a divalent zinc cation present in the matrix by adding zinc chloride
  • a formulation of HA and of CHITO comprising 90% co-crosslinked HA-CHITO phase and 10% non-crosslinked (linear) phase based on HA-CHITO is prepared.
  • the concentrations of HA and CHITO are respectively 0.9% and 0.1% by weight relative to the total weight of the matrix.
  • the crosslinked phase of HA-CHITO is prepared as previously described in connection with test No. 4.
  • a linear phase with HA and CHITO is prepared as previously described in connection with test No. 4, except that after complete dissolution of sodium hyaluronate (NaHa) and carboxymethyl chitosan, a divalent zinc cation is added to the matrix by incorporating zinc chloride (ZnCl 2 ) into the solution (by means of a dispersion).
  • ZnCl 2 zinc chloride
  • crosslinked and linear (non-crosslinked) phases are then mixed, respecting a 9:1 ratio.
  • the biocompatible cross-linked matrix product thus obtained has a density of approximately 1, and is then transferred into 1 mL glass syringes.
  • the glass syringes are then subjected to heat treatment as described above, by autoclaving with a sterilization plate for 1 minute at 131°C.
  • the total duration of the heat treatment including the temperature rise, the plateau and the cooling is approximately 22 to 23 minutes.
  • Test No. 6 Formulation of a biocompatible product with a co-crosslinked matrix HA and CHITO, with a divalent zinc cation present in the matrix by adding zinc sulphate
  • a formulation of HA and CHITO comprising 90% co-crosslinked HA-CHITO phase and 10% non-crosslinked (linear) phase based on HA-CHITO is prepared.
  • the concentrations of HA and CHITO are respectively 0.9% and 0.1% by weight relative to the total weight of the matrix.
  • the crosslinked phase of HA-CHITO is prepared as previously described in connection with test No. 4.
  • a linear phase with HA and CHITO is prepared as previously described in connection with test No. 4, except that after complete dissolution of sodium hyaluronate (NaHa) and carboxymethyl chitosan, a divalent zinc cation is added to the matrix by incorporating zinc sulphate (ZnSO 4 ) into the solution (by means of a dispersion).
  • ZnSO 4 zinc sulphate
  • crosslinked and linear (non-crosslinked) phases are then mixed, respecting a 9:1 ratio.
  • the biocompatible cross-linked matrix product thus obtained has a density of approximately 1, and is then transferred into 1 mL glass syringes.
  • the glass syringes are then subjected to a heat treatment as described above, by passage through an autodave with a sterilization tray for a period of 1 minute at 131°C.
  • the total duration of the heat treatment including the rise in temperature, the plateau and the cooling is approximately 22 to 23 minutes.
  • viscosities of formulations 1, 2a to 2c, 3, 4a, 4b, 5a to 5c and 6a to 6c were measured using a Discovery hybrid rheometer "DHR2" from the company TA Instruments as previously explained, and this before and after application of the previously explained heat treatment (sterilization with a plateau lasting 1 minute at a temperature of 131°C, total duration of the heat treatment including the rise in temperature, the plateau and the cooling is approximately 22 to 23 minutes).
  • DHR2 Discovery hybrid rheometer
  • a fourth observation, based more particularly on formulations 4b, 5a to 5c, 6b and 6c, is that the addition of a divalent zinc cation in a coreticulated matrix of HA and of CHITO according to a concentration between approximately 0.005% and about 0.06% makes it possible to obtain a viscosity after heat treatment almost close to the viscosity before heat treatment (formulations 5a, 5b), or even greater than the viscosity before heat treatment (formulations 4b, 5c, 6b and 6c).
  • the present invention which makes it possible to obtain a high viscosity after heat treatment, even higher than the viscosity before heat treatment, proves to be very valuable for the prevention and/or treatment of pathologies which can be improved or avoided by :
  • the present invention which makes it possible to obtain a high viscosity after heat treatment, even higher than the viscosity before heat treatment, also proves to be very valuable for a method for treating osteoarthritis, or for repairing a cartilage defect, the composition being for example formulated for administration by injection into synovial fluid or for implantation into cartilage after mixing with blood, or for a method of treating dry eye.
  • the present invention which makes it possible to obtain a high viscosity after heat treatment, even higher than the viscosity before heat treatment, also proves to be very valuable for use in a treatment method in therapy, in surgery, or cosmetics, including in particular treatment in rheumatology, ophthalmology, gynecology, aesthetic medicine, plastic surgery, internal surgery, orthopedic surgery, for the prevention of post-surgical tissue adhesions, in dermatology.
  • the present invention which makes it possible to obtain a high viscosity after heat treatment, even higher than the viscosity before heat treatment, also proves to be very valuable for use in a therapeutic treatment of an eye syndrome. dryness, corneal damage or eye or joint inflammation.
  • the present invention which makes it possible to obtain a high viscosity after heat treatment, or even higher than the viscosity before heat treatment, also proves to be very valuable for use in a therapeutic treatment during which said composition is applied by instillation. on the ocular surface to prevent or combat corneal damage or dry eye syndrome, in particular for the purpose of lubricating or regenerating the ocular surface.
  • composition of ophthalmic drops comprising a biocompatible product with a co-crosslinked matrix of HA and of CHITO as described previously.
  • Biocompatibility trials and tests were carried out by intracutaneous injections of doses of 0.2 mL on the backs of rabbits at separate sites. The sites were observed immediately after injection. Observations were made in terms of erythema and edema after 24h (1 day), 48h (2 days), 72h (3 days), 7 days and 14 days.
  • - sample A a biocompatible product according to formulation 2a, the divalent zinc cation being added to the matrix by incorporating zinc gluconate according to a zinc gluconate concentration of 20 ppm (i.e. a concentration of divalent zinc cation in the matrix 0.002%),
  • - sample B a biocompatible product according to the invention and differing from formulations 4a and 4b only by a concentration of zinc gluconate of 20 ppm (i.e. a concentration of divalent zinc cation in the matrix of 0.002%), it being specified that the carboxymethyl chitosan is of plant (fungal) origin,
  • - sample C a biocompatible product according to the invention and differing from formulations 4a and 4b only by a concentration of zinc gluconate of 20 ppm (i.e. a concentration of divalent zinc cation in the matrix of 0.002%), it being specified that the carboxymethyl chitosan is of animal origin,
  • - sample D a product marketed under the PERFECTHA® DERM brand (batch number: 190625-2) from the company Sinclair France SAS,
  • - sample F a solution of sodium chloride (physiological serum) at 9 g/L (ie 0.9% by weight by volume).
  • Tests and ocular irritation tests were carried out (in adaptation of the ISO 10993 standard - part 10) by instillation of doses of 0.1 mL of samples to be tested into the lower conjunctival sac of the left eye of rabbits while a dose of 0.1 mL of a solution of sodium chloride (physiological serum) at 9 g/L (i.e. 0.9% by weight by volume) was instilled as a control in the lower conjunctival sac of the right eye of said rabbits. Observations were made in terms of ocular reactions after 1 h, 24 h (1 day), 48 h (2 days) and 72 h (3 days). Each sample was tested on two rabbits.
  • - sample G a biocompatible product according to formulation 2a, the divalent zinc cation being added to the matrix by incorporating zinc gluconate according to a zinc gluconate concentration of 20 ppm (i.e. a concentration of divalent zinc cation in the matrix 0.002%),
  • - sample H a biocompatible product according to the invention and differing from formulations 4a and 4b only by a concentration of zinc gluconate of 20 ppm (i.e. a concentration of divalent zinc cation in the matrix of 0.002%), it being specified that the carboxymethyl chitosan is of plant (fungal) origin,
  • - sample I a biocompatible product according to the invention and differing from formulations 4a and 4b only by a concentration of zinc gluconate of 20 ppm (i.e. a concentration of divalent zinc cation in the matrix of 0.002%), it being specified that the carboxymethyl chitosan is of animal origin.
  • product with adaptive viscoelastic behavior is meant a product having:
  • biocompatible products according to the present invention which were tested (after heat treatment) are:
  • sample L (HYLO-FORTE® from the company Ursapharm Arzneistoff GmbH) shows a viscoelastic behavior that is clearly more adaptive, its viscosity remains low over the entire range of shear rates tested.
  • formulations according to the present invention all have a viscosity which is high at low shear rate and which decreases fairly regularly (more or less quickly) down to a viscosity significantly lower at high shear rates.
  • the formulations according to the invention thus have an adaptive viscoelastic behavior making them suitable for use in an ophthalmic drop composition, and the concentration of divalent zinc cation in the matrix and the rate of crosslinking of the matrix make it possible to adapt the viscosity to the desired use.
  • the formulations according to the present invention are thus particularly interesting for a therapeutic treatment by instillation on the ocular surface to prevent or fight against a corneal lesion or a dry eye syndrome, in particular with the aim of lubricating or regenerating the ocular surface.
  • the viscosity of the formulations according to the invention is markedly higher than the viscosity of the products available on the market.

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EP22719360.4A 2021-04-26 2022-04-19 Produit biocompatible a matrice comprenant un polysaccharide et du chitosane co-reticules Pending EP4329713A1 (fr)

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FR2927255B1 (fr) * 2008-02-07 2011-08-12 Keysan Consulting Produits injectables biocompatibles a liberation de zinc et/ou de sel de saccharide sous forme de zinc et leurs utilisations.
US10898613B2 (en) * 2016-09-21 2021-01-26 Nestlé Skin Health Sa Hyaluronic acid gel with a divalent zinc cation
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