WO2020095079A1 - Injectable composition containing hyaluronic acid, intended for the body - Google Patents

Injectable composition containing hyaluronic acid, intended for the body Download PDF

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Publication number
WO2020095079A1
WO2020095079A1 PCT/IB2018/001235 IB2018001235W WO2020095079A1 WO 2020095079 A1 WO2020095079 A1 WO 2020095079A1 IB 2018001235 W IB2018001235 W IB 2018001235W WO 2020095079 A1 WO2020095079 A1 WO 2020095079A1
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Prior art keywords
composition
hyaluronic acid
composition according
syringe
hydrogel
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PCT/IB2018/001235
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French (fr)
Inventor
Samuel Gavard Molliard
Original Assignee
Kylane Laboratoires Sa
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Priority to PCT/IB2018/001235 priority Critical patent/WO2020095079A1/en
Publication of WO2020095079A1 publication Critical patent/WO2020095079A1/en

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    • 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

Definitions

  • the subject of the present invention is: a sterile injectable composition in the form of a hydrogel containing crosslinked hyaluronic acid, or one of its salts,
  • Hyaluronic acid is a polysaccharide formed by the repetition of a disaccharide unit composed of D-glucuronic acid and N-acetylglucosamine. Its structure is linear and without species specificity. Hyaluronic acid is widely distributed in living human and animal organisms, in which it plays many biological functions such as, for example, controlling the rate of hydration or maintaining the viscoelasticity of fluids or tissues. It is found in particular in high concentration in the synovial fluid, the vitreous body of the eye and in the dermis. A 70 kg human being has approximately 15 g of hyaluronic acid, half of which is contained in the skin and this quantity decreases with aging.
  • Hyaluronic acid has a low half-life in living organisms (less than 1 week).
  • cross-linking makes it possible to considerably increase the lifespan (also called persistence) of hyaluronic acid in vivo, but it also makes it possible to modify its mechanical and rheological properties by making it in particular more elastic, which then makes it possible to increase its capacity. to create volume once injected into the desired tissues.
  • a hydrogel based on crosslinked hyaluronic acid has for example the capacity to fill in wrinkles or even to restore the volumes of the face over a period of several months.
  • injectable cross-linked hyaluronic acid has become the treatment of choice for correcting facial volumes in aesthetic medicine.
  • ASAPS American Society for Aesthetic Plastic Surgery
  • injections of crosslinked hyaluronic acid are carried out by authorized and trained doctors, and in particular surgeons and dermatologists.
  • the product is administered to patients using pre-filled syringes usually containing 1 ml of sterile hydrogel and treatment usually requires less than 2 ml to fill the target facial tissue and thus obtain the desired cosmetic correction.
  • the aim of the present invention is therefore to propose a new injectable composition based on cross-linked hyaluronic acid for treating the body at the level of the subcutaneous tissues; bioresorbable, temporary (non-permanent), reversible and minimally invasive composition which considerably meets the needs of doctors and their patients compared to the injectable compositions based on cross-linked hyaluronic acid of the prior art.
  • This new composition aims to allow the emergence of a solution with a high level of security, performance, easy to use and inducing a high satisfaction for doctors as for patients.
  • the purpose of this new composition is to be able to be used both for aesthetic applications and for medical applications in the field of plastic and reconstructive medicine.
  • the present invention aims precisely to provide a new composition in the form of a sterile injectable hydrogel containing crosslinked hyaluronic acid, or one of its salts; composition packaged in a syringe having a useful volume equal to 5 ml ⁇ 2 ml.
  • This new composition specifically designed for the needs of the treatment of subcutaneous tissues of the body, that is to say for the parts of the human body excluding the head and the face, has characteristics which significantly differentiate it from the compositions of the prior art.
  • a first essential distinguishing characteristic is the volume of the syringe used.
  • the injectable composition according to the invention is packaged in a syringe having a useful volume of 5 ml ⁇ 2 ml; advantageously 5 ml.
  • the compositions of the prior art they are packaged in syringes whose useful volume is greater than or equal to 10 ml, and more precisely 10 ml, 20 ml or 50 ml.
  • body treatment requires much higher quantities / doses ranging from several tens of milliliters to several hundred milliliters.
  • compositions of the prior art it therefore seems relevant and practical to package an injectable composition based on crosslinked hyaluronic acid for use in the body in a syringe with a high volume greater than or equal to 10 ml. . Nevertheless, surprisingly and contrary to what a person skilled in the art would do, the composition of the present invention is imperatively packaged in a syringe having a useful volume significantly lower than currently existing solutions.
  • a second essential differentiating characteristic, combined with the first relating to the useful volume of the conditioning syringe, is that the crosslinked hyaluronic acid has a structure called “monophasic” (and “cohesive”) and not “biphasic” (and “non-cohesive” ”) As in the case of the compositions of the prior art.
  • compositions existing in the field of body treatment are called biphasic and non-cohesive because to make them injectable, the manufacturer fragments the crosslinked hyaluronic acid, that is to say that it voluntarily generates particles of crosslinked hyaluronic acid (of the order of 1000 particles per 1 ml of composition; particles having a diameter of more than 1000 micrometers), this so that the product can be extruded more easily through the needle or the cannula used when the doctor pushes the plunger of the syringe to administer the product to his patient.
  • crosslinked hyaluronic acid particles have a particularly high degree of crosslinking (degree of modification within the particle often greater than 15 mol%), a semi-solid consistency, high rigidity / elasticity (elasticity G 'at 1 Hz within the particle often greater than 1000 Pa), and therefore a significantly higher probability of being perceived as a foreign body by the organism (biphasic crosslinked hyaluronic acid being on the one hand in the form of particles, which is not the case with hyaluronic acid in its natural state in the human body, and on the other hand, it is more modified by crosslinking and therefore much less close to the native hyaluronic acid present in the body ).
  • composition is also called non-cohesive because if said composition is introduced into water, the crosslinked particles disperse easily and quickly (proof of their high capacity to dissociate and therefore of their non-cohesive characteristic).
  • the composition according to the invention does not consist of crosslinked hyaluronic acid of biphasic and non-cohesive structure (thus allowing a reduction in the strength d extrusion necessary to inject the product due to its fragmentation into particles).
  • the composition according to the invention has a so-called monophasic and cohesive structure.
  • the crosslinked hyaluronic acid according to the invention then has a lower degree of crosslinking than that of the crosslinked hyaluronic acid particles of a so-called biphasic product, thus allowing it to be closer to endogenous hyaluronic acid but also d '' have biophysical properties closer and appropriate to the soft tissues of the body.
  • hyaluronic acid cross-linked monophasic therefore remains in the form of a so-called unique and flexible phase, and this phase has a significantly greater cohesiveness than that of a product known as biphasic (introduced into water, such a monophasic product dissociates much less easily and quickly than a product known as biphasic, allowing it to conserve more its unity, its consistency and its structure, and therefore its rheological and mechanical properties).
  • the monophasic structure of the composition according to the invention makes it possible to benefit from a higher level of security and from biophysical properties more suited to the tissues of the body, and in particular of the subcutaneous tissues, compared to the compositions based hyaluronic acid of the prior art for applications on the body.
  • composition according to the invention can be extruded / injected easily, and in particular with a cannula or needle of small diameter, which is not possible or very difficult to do with solutions based on acid cross-linked hyaluronic from the prior art for the body.
  • the composition according to the invention can be injected into the subcutaneous tissues of the body extremely easily with a 12G to 16G cannula but it can also be easily injected with an 18G cannula at 21G.
  • the composition contains hyaluronic acid or one of its salts, and in particular its physiologically acceptable salts such as the sodium, calcium, zinc, potassium salts, advantageously the salt of sodium.
  • the hyaluronic acid can be of animal origin or obtained by bacterial fermentation. It can have a molecular mass of a few daltons to several million daltons, advantageously from approximately 0.01 to 5 million daltons, still advantageously from approximately 0.1 to 3.5 million daltons.
  • the composition may be based on a derivative of hyaluronic acid, that is to say based on a molecule obtained by modifying chemically, or by any other route, the hyaluronic acid molecule.
  • the total concentration of hyaluronic acid, or one of its salts is between 0.001 and 70 mg / ml, between 0.01 and 50 mg / ml, between 1 and 40 mg / ml, between 5 and 35 mg / ml, between 8 and 33 mg / ml, between 9 and 30 mg / ml, between 10 and 29 mg / ml, between 11 and 28 mg / ml, between 12 and 27 mg / ml, between 12 and 26 mg / ml, advantageously between 12 and 25 mg / ml.
  • the hyaluronic acid contained in the composition is crosslinked, totally or partially, preferably according to the crosslinking techniques described in the prior art.
  • the crosslinking agent (s) involved in the crosslinking can be identical or different. They are generally bi- or poly-functional crosslinkers of different types and they can for example be selected from divinylsulfone, bi- or poly-functional epoxies, carbodiimides and formaldehyde.
  • Agents of the bi- or poly-functional epoxy family are preferably chosen and in particular 1,4-butanedioldiglycidylether (BDDE), diepoxy-octane or 1,2-bis- (2,3-epoxypropyl) -2 , 3-ethylene.
  • BDDE 1,4-butanedioldiglycidylether
  • Crosslinking temperatures are generally between about 15 ° C and 60 ° C and the durations of crosslinking are generally several hours, advantageously more than 1 hour until approximately 24 hours.
  • the degree of crosslinking of hyaluronic acid, or one of its salts, in the composition according to the invention is advantageously between 1% and 12%, preferably between 2% and 10%, preferably between 3% and 8% .
  • the degree of crosslinking is defined as being the percentage by mass of the molar ratio of the crosslinking agent to the hyaluronic acid monomer.
  • crosslinker used for bridging the hyaluronic acid chains is a molecule generally having a non-negligible level of toxicity.
  • the residual crosslinker after crosslinking (that which has not reacted with hyaluronic acid during crosslinking) must be eliminated as much as possible during the purification of the hydrogel (generally by dialysis in a physiological aqueous solution) so as to have an injectable composition having the best possible level of safety for the patient.
  • the composition according to the invention must imperatively have a residual level of this compound of less than 2 ppm, advantageously less than 1.5 ppm, advantageously less at 1.0 ppm, advantageously less than 0.5 ppm, advantageously less than 0.1 ppm.
  • hyaluronic acid is totally or partially crosslinked.
  • the composition according to the invention advantageously comprises a mixture of more than 80% by mass of hyaluronic acid in the crosslinked form and of less than 20% by mass of hyaluronic acid ⁇ in the non-crosslinked form.
  • the mass fraction of hyaluronic acid in the non-crosslinked form is less than or equal to 15% of the total mass of hyaluronic acid in the finished product.
  • the majority of the composition is water, hence the qualifier hydrogel or aqueous composition for the new composition according to the invention.
  • the water mass in the composition according to the invention is greater than 51% of the total mass, advantageously greater than 60% of the total mass, advantageously greater than 70% of the total mass, advantageously greater than 75% of the total mass , advantageously greater than 85% of the total mass, advantageously greater than 95% of the total mass.
  • a buffer solution is advantageously used in particular to better control the pH and the osmolarity of the formulation throughout its shelf life. We can for example cite the use of a buffer based on sodium chloride and phosphate salts.
  • the sterile injectable composition advantageously has a physiological osmolarity, that is to say an osmolarity of between 200 and 400 mOsm / kg, and a pH of between 6.0 and 7.9.
  • the sterile injectable composition may contain a local anesthetic such as lidocaine hydrochloride or any other compound making it possible to limit the patient's pain during the administration of the product to the patient.
  • a local anesthetic such as lidocaine hydrochloride or any other compound making it possible to limit the patient's pain during the administration of the product to the patient.
  • the composition is sterile and it is advantageously sterilized with heat, preferably with moist heat (also called steam autoclaving).
  • the moist heat sterilization is carried out at a temperature above 100 ° C, advantageously above 110 ° C, advantageously above 120 ° C.
  • the sterilization time can range from a few seconds to several minutes. Examples include the following moist heat sterilization cycles: 121 ° C for 20 minutes or 125 ° C for 7 minutes or 127 ° C for 4 minutes or 130 ° C for 3 minutes.
  • heat sterilization is advantageously selected because it grants a very high level of sterility to the chosen composition, which then makes it possible to aim for a high level of safety for the treated patient.
  • the injectable composition is packaged in a syringe having a useful volume equal to 5 ml ⁇ 2 ml.
  • the useful volume of the syringe used is between 3.0 ml and 7.0 ml.
  • the composition according to the invention is packaged in a syringe having a useful volume of 5 ml.
  • This syringe can be made of plastic material or glass material, preferably plastic material and more precisely Cyclo-Olefin-Copolymer (COC) or Cyclo-Olefin-Polymer (COP) material.
  • This syringe advantageously consists of a luer-lock integrated into the body of the syringe, that is to say directly molded with the body of the syringe, thus limiting the risk of rupture of the luer-lock.
  • the syringe has a coating on its internal walls (preferably siliconization), this facilitating the sliding of the piston seal and thus reducing the extrusion forces of the composition.
  • the syringe is equipped with a plunger rod and a finger support, made from plastic materials (to facilitate rigidity and stability during the injection) to improve the doctor's comfort and the precision of his injection.
  • the syringe is also equipped with a plunger seal and an elastomeric plastic stopper, allowing the product to be hermetically sealed, especially during the sterilization process and the storage of the composition during its expiration period.
  • the injectable composition has a volume of gel based on cross-linked hyaluronic acid of between 3 ml and 7 ml in the syringe.
  • This gel volume is advantageously equal to 5 ml.
  • the sterile composition is administered to the patient by injection through a cannula or a needle.
  • the diameter of the cannula is advantageously between 18G and 21G and that of the needle between 21G and 25G.
  • the extrusion force (in Newtons N) required to inject the gel through the cannula or the needle, at a speed of 13 mm / min, is advantageously between 5 N and 40 N, advantageously between 10 N and 30 N .
  • the sterile injectable composition based on crosslinked hyaluronic acid has an elasticity G 'at 1 Hz (and at 1% deformation) advantageously between 50 Pa and 450 Pa, preferably between 60 Pa and 300 Pa, preferably between 70 Pa and 250 Pa.
  • the viscoelastic properties of a gel based on hyaluronic acid are effectively essential for product safety and efficacy, whether for uses in aesthetics or in plastic and reconstructive medicine.
  • the sterile injectable composition of monophasic structure advantageously has an elasticity G 'at 1 Hz:
  • the composition is stable at room temperature and its shelf life can therefore reach more than 24 months under these conditions.
  • the biocompatibility of the composition conforms to standard ISO 10993.
  • the monophasic structure of the composition combined with its suitable rheological properties and its very high purity, largely justifies the excellent tolerance of the hydrogel. in the tissues subcutaneous of the body, in the long term, even if the hydrogel is injected in large quantities in the treated area.
  • the injectable composition makes it possible to obtain clinical benefits in the area of the body treated over an average period which can range from 6 months to 24 months, whether for aesthetic applications or for therapeutic applications.
  • the composition according to the invention contains at most 45% by mass, advantageously at most 30% by mass, advantageously at most 20% by mass, advantageously at most 10% by mass, advantageously at most 5 % by mass, advantageously at most 2.5% by mass, advantageously at most 1% by mass, of one or more compounds other than water and hyaluronic acid, or one of its salts.
  • the composition according to the invention contains one or more active substances of natural or synthetic origin with or without pharmacological action, such as, for example, antioxidants, anti-inflammatories, antiseptics, antibacterials, antifungals, anticancer drugs, proteins, hormones, amino acids, fatty acids, biologically acceptable lipids, alone or in combination.
  • active substances are either dispersed in the hydrogel, or grafted to one or more of the hydrogel polymers, either contained / encapsulated in liposomes / niosomes dispersed in the hydrogel, or contained / encapsulated in another material itself dispersed within the hydrogel.
  • the composition according to the invention contains one or more compounds of biological origin such as cells, enriched platelets, genes, DNA fragments or growth factors. These compounds are preferably dispersed in the hydrogel, but they can also be grafted to one or more of the hydrogel polymers or contained / encapsulated in liposomes / niosomes dispersed in the hydrogel or contained / encapsulated in another material itself. even dispersed within the hydrogel.
  • the composition according to the invention contains polymers which are dispersed within the crosslinked matrix of the hydrogel. Mention may be made, for example, of polymers of the polysaccharide family, polyesters, polyanhydrides, polyphosphazenes, poly-e-caprolactones, cellulose and its derivatives, polylactic acids and their derivatives, polyvinyl acids, polyacrylamides, N-vinyl pyrrolidone and biologically acceptable acrylic polymers and derivatives. According to one aspect of the invention, the composition according to the invention contains mineral substances which are dispersed within the crosslinked matrix of the hydrogel. Mention may be made, for example, of hydroxyapatite or tricalcium phosphates such as b tricalcium phosphate.
  • the composition according to the invention is mixed with one or more other substances, preferably sterile, capable of bringing a benefit to the body, just before its administration in the patient.
  • the mixing is then carried out by the end user, that is to say by the doctor, according to an appropriate method using one or more mixing devices making it possible to produce a satisfactory mixture and to maintain sterility.
  • the new sterile injectable composition disclosed in the present invention aims to give birth to a new minimally invasive solution, that is to say non-surgical (and not involving the use of an operating theater), for treatment of the body by injection into the subcutaneous tissues:
  • the injectable composition according to the invention has the following considerable advantages compared to the compositions based on cross-linked hyaluronic acid of the prior art for treating the subcutaneous tissues of the body of a patient:
  • the injectable composition according to the invention is easily injectable through a cannula or a needle, which then makes it possible to be able to use a cannula or needle of smaller diameter.
  • the compositions of the prior art are generally administered with a large 12G cannula
  • the present composition given its characteristics, can be injected with a significantly finer cannula from 18G to 21G.
  • the diameter of the incision is considerably reduced, which then makes it possible to proceed with the act of injection in a city office (as in the case of facial treatment) and not in the operating room, and without anesthesia general.
  • the procedure is then considerably shorter, less risky, less complex and less costly,
  • the possibility of injecting the composition according to the invention through a cannula or needle significantly thinner compared to the solutions of the prior art makes it possible to reduce the pain of the patient at the injection, the risk of contamination linked to the size of the incision at the point of entry as well as the risk of scars,
  • composition according to the invention is very ergonomic due to a smaller syringe, then allowing the doctor to be much more precise in his treatment during the injection of the product but also to have less fatigue of the hand that performs the act of injection,
  • the volumes injected can be very large and require more than one syringe for a treatment session, the excellent ergonomics of the composition according to the invention (syringe size more suited to the doctor's hand compared to a larger syringe 10 ml, 20 ml or 50 ml) allows you to easily and quickly replace the empty syringe with a new full syringe, while keeping the cannula / needle in the area of the body that is being treated,
  • composition according to the invention significantly reduces the risk of overdose due to the lower volume of hydrogel contained in the syringe. Indeed, in the case of the compositions of the prior art based on crosslinked hyaluronic acid, the large syringe volumes of 10 ml, 20 ml or 50 ml may encourage the doctor to use the entire syringe in the patient. treated when it is not necessary. Therefore, in the case of the composition according to the invention, the adjusted volume of 5 ml ⁇ 2 ml makes it possible to treat the patient in a more reasoned and proportioned manner,
  • the composition according to the invention also makes it possible to significantly reduce the risk of re-using a syringe partially used for a new subsequent application, this taking into account the lower volume of composition that it contains.
  • the large syringe volumes of 10 ml, 20 ml or 50 ml can encourage the doctor to use only a fraction of the composition and keep the rest of the product ( having lost its sterility) for later use. These practices can create serious risks of contamination and infection for the patient.
  • the volume of 5 ml ⁇ 2 ml is adjusted to the treatment of the areas requiring low volumes, which then allows the complete use of the composition in a single treatment session, and therefore does not encourage the doctor to keep a partially used syringe for later application, -
  • the monophasic (and therefore cohesive) structure of the composition according to the invention makes it possible to have a product which distributes and positions itself significantly better in the subcutaneous tissues compared to the biphasic compositions of the prior art, thus allowing d '' obtain a more homogeneous and natural clinical result (tissue flexibility and smooth surface appearance), thus more respecting the biomechanics of the tissues in the treated area,
  • the monophasic structure combined with specific rheological properties of the composition according to the invention, also makes it possible to have a product with a higher level of safety which creates more volume because the product disperses less (because higher cohesiveness) during injection into fatty tissue but also during the months following injection of the product (risk of migration considerably reduced).
  • this new injectable composition allows the following advantages:
  • the doctor can carry out one or more touch-ups to improve the clinical results, following the first injection session, if necessary (in the doctor's office and therefore not in the operating room as in the case of surgery) ,
  • the doctor has the possibility of improving the results of a surgery (implant, fat transfer or other) by completing the post-surgery results (for example, correction of irregularities or skin depression) while avoiding having to return to the operating room to have another surgery.
  • the present invention relates, according to a second of its aspects, to a process for preparing the new sterile injectable composition described above.
  • the process for preparing the composition according to the invention is characterized by the following successive steps: a) preparation of a hydrogel based on cross-linked hyaluronic acid, or one of its salts, according to the conditions of the invention,
  • Step (a) generally begins with the dissolution of the hyaluronic acid and then by its crosslinking, using a crosslinker, and it generally ends with the purification of the hydrogel obtained.
  • crosslinking step of hyaluronic acid is understood to mean the step making it possible to bridge the chains of hyaluronic acid to one another by covalent bonds.
  • the crosslinking step of hyaluronic acid begins when the crosslinker is brought into contact with hyaluronic acid and ends when a person skilled in the art considers that the reaction kinetics of bridging chains hyaluronic acid by the crosslinker has reached a negligible level.
  • Purification of the hydrogel makes it possible to remove the undesirable molecules from the prepared gel and in particular the crosslinker residues, following crosslinking.
  • This purification is carried out according to techniques well known to those skilled in the art, for example by dialysis baths, by washing with a continuous flow of water or by precipitation.
  • Step (b) consists in filling the hydrogel prepared during step (a) in syringes of 5 ml ⁇ 2 ml.
  • the syringe filling operation can be carried out by manual method or using a semi-automatic or automatic filling machine.
  • Step (c) consists in sterilizing the composition by techniques well known to those skilled in the art; sterilization being advantageously carried out with moist heat by autoclaving.
  • An advantageous process according to the invention for the manufacture of a sterile aqueous injectable composition according to the invention comprises at least the following steps: preparation of an aqueous solution of hyaluronic acid,
  • hydrogel for example by dialysis in a physiological solution, packaging in syringes of 5 ml ⁇ 2 ml, sterilization.
  • the present invention relates, according to a third of its aspects, to the use in humans, at the level of the body exclusively (this therefore excluding the head and the face), of the new sterile aqueous injectable composition described above, for aesthetic applications or therapeutics in plastic and reconstructive medicine.
  • the composition according to the invention is used at the level of the body by deep injection with a cannula or a needle in the tissues, and in particular in the subcutaneous tissues. In order to obtain an optimal clinical result, it is recommended that the injection be carried out in an area where the thickness of the tissues (including the subcutaneous fatty tissues) is sufficient. It is important to specify that the administration of the composition according to the invention is prohibited in the blood vessels and in the intra-articular tissues and it is not recommended in the muscular tissues or in the context of injections which are too superficial to the surface of the body.
  • composition according to the invention is used on the body to: fill, increase or restore volumes,
  • composition according to the invention is particularly suitable:
  • composition according to the invention can be used in the context of an aesthetic treatment of the body, for example to correct the effects linked to aging or also to increase areas of the body which require it.
  • the composition can be used in the context of a therapeutic treatment of the body in plastic or reconstructive medicine, for example to treat structural defects of congenital or medical origin (illness, trauma, post-surgery, etc.). These include the treatment of scar tissue on the surface of the body, the restoration of body volumes in patients with diseases such as HIV, the reconstruction of areas of the body that have been traumatized or surgically extracted, the correction of cavities such as example a cavity formed following an orthopedic surgery of the shoulder, the correction of post-surgical imperfections on the surface of the body such as for example irregularities or cutaneous depressions following a liposuction or a lipofilling.
  • the present invention relates, according to a fourth of its aspects, to a method of treatment for aesthetic or therapeutic purposes in humans, exclusively at the level of the body (this therefore excluding the head and the face), by deep injection with a cannula or a needle in the subcutaneous tissues, of the composition according to the invention described above for:
  • - restore / correct body volumes such as for example to increase the volume in the buttocks, breasts, calves, chest, cleavage, back, thighs, legs, belly, hips, shoulders , arms, forearms, hands, feet and genitals.
  • this invention relates in particular to a therapeutic or non-therapeutic method for increasing, correcting, restoring or creating volume in the body of a patient, characterized by:
  • the area to be treated at the body level is selected from the group comprising the buttocks, breasts, calves, chest, cleavage, back, thighs, legs, stomach, hips, shoulders, arms , forearms, hands, feet and genitals.
  • the technique for injecting the composition according to the invention may vary depending on the body area to be treated, the exact depth of injection into the subcutaneous tissues, the amount to be administered, and the habits and preferences of the doctor. .
  • the doctor Before injecting the composition according to the invention, the doctor is recommended to carry out a rigorous disinfection of the area of the body which he wishes to treat in order to avoid contamination of the hydrogel injected with bacteria and / or other compounds foreign to the body (for example, traces of cosmetic products).
  • Local anesthesia of the area to be treated by injection and / or by application of a topical anesthetic, may be performed by the doctor.
  • a cannula or needle is then connected to the syringe of the composition according to the invention, following the indications provided in the instructions for use.
  • the composition according to the invention is administered slowly, regularly and under control, into the subcutaneous tissues of the body area treated. The doctor then carefully observes the induced tissue increase, but also any unwanted sign potentially generated by the injection such as discoloration of the skin or too much pain in the patient, requiring action by the doctor (such as a partial stop or total of the injection in progress).
  • Certain zones are treated by injecting the composition according to the invention at a single entry point, while other zones are treated by injecting at different entry points.
  • the doctor When the doctor considers having injected enough of the composition according to the invention, he is recommended to carry out a gentle massage of the treated area so that the hydrogel can be positioned in the most appropriate and harmonious way possible in the tissues under - cutaneous.
  • the amounts administered of the composition according to the invention can range from a few milliliters (as for example in the case of the treatment of a scar or a post-surgical cavity / depression on the body), to several hundred milliliters (as for example in the case of increase in the volume of the buttocks or breasts), depending on the exact indication intended. In general, a patient should not receive more than 600 ml of the composition in a year.
  • the treatment of the area of the body targeted by the doctor can be carried out during a single session or during several injection sessions.
  • New injections (called “touch-ups") of smaller volumes compared to the initial injection can be performed over time by the doctor in order to clinically optimize the result obtained and / or to maintain the desired clinical effect over time. months.
  • Sodium hyaluronate, lidocaine hydrochloride and all the other compounds used in the following examples have a high level of purity.
  • the phosphate buffer solution used has the following composition: 8.5 g of NaCl, 0.041 g of NaH 2 P0 4 dihydrate, 0.292 g of Na 2 HP0 4 dihydrate in 1 liter of water for injection.
  • the rheological properties (measurement of the elastic modulus G ') of the gels are measured at 25 ° C using a constrained rheometer (TA HR-1) and a cone / plane geometry 4 cm-2 ° with an air gap of 1000 micrometers.
  • the concentration of residual BDDE in the gels is measured by HPLC-MS.
  • the extrusion forces of the gels through the cannulas are measured on a compression bench, at a speed of 13 mm / min, using a force sensor 200 N.
  • GEL1 gel In 28.85 g of GEL1 gel, a powder of lidocaine hydrochloride is added and the gel is mixed manually with a spatula for 10 minutes. A solution of uncrosslinked hyaluronic acid (molecular weight approximately equal to 1.5 MDa) at 35 mg / ml is added and the gel is mixed manually with a spatula for 10 minutes. The final concentration of the gel and the lidocaine hydrochloride is adjusted with a phosphate buffer solution. The gel is mixed manually with a spatula for 10 minutes. Let GEL1A be the gel thus obtained. The hyaluronic acid concentration of GEL1A is 26 mg / ml.
  • the concentration of lidocaine hydrochloride in GEL1A is 3 mg / ml.
  • GEL1A gel is packaged in 5 ml plastic syringes (containing 5 ml of gel) and then sterilized in an autoclave at 127 ° C for 4 minutes.
  • GELIBs composition according to the invention
  • GEL1C a phosphate buffer solution is added in order to adjust the final concentration of the gel.
  • the gel is mixed manually with a spatula for 10 minutes.
  • GEL1C be the gel thus obtained.
  • the hyaluronic acid concentration of GEL1C is 9 mg / ml.
  • Example 2 Characterization of the GELIBs composition according to the invention
  • the GELIBs composition according to the invention has the following physico-chemical and rheological characteristics:
  • the residual BDDE concentration is less than 1 ppm
  • the single-phase structure of the GELIBs composition according to the invention is observed and characterized by the following tests, compared to NASHA ® injectable composition (biphasic structure) based on crosslinked hyaluronic acid of the prior art:
  • the GELIBs composition according to the invention has a continuous and homogeneous structure (a single phase ),
  • NASHA ® composition has a discontinuous and heterogeneous structure (visible particles).
  • composition GELIBs according to the invention has a continuous and homogeneous network (not visible particles),
  • composition NASHA ® presents a discontinuous and heterogeneous network (visible particles).
  • o the GELIBs composition according to the invention spreads out in a homogeneous and cohesive way (remains in a single piece) presenting a flexible and malleable aspect
  • o NASHA ® composition ranges from heterogeneous and cohesively (creation of fragments and clusters gel) having a semi-solid appearance (hard particles dispersed in a very fluid phase).
  • composition GELIBs although more voluminous after its swelling, retains its gel structure and does not undergo any change in appearance during agitation: it has a continuous and homogeneous structure (single phase), o NASHA ® composition partially dispersed due to its swelling, completely disperses during agitation: semi-solid particles suspended in the liquid are visible.
  • composition according to the invention is indeed monophasic (cohesive). It has a homogeneous structure and a flexible appearance, unlike a biphasic (non-cohesive) injectable composition based on cross-linked hyaluronic acid of the prior art, which itself has a heterogeneous structure (presence of particles) and a semi- solid.
  • Example 3 Method of treating a patient using the composition according to the invention
  • a 28-year-old patient with a body mass index of 18.4 kg 2 / cm was injected by a doctor in a city practice environment (and therefore not in the operating room, without general anesthesia), in the subcutaneous tissues with the composition according to the invention (sterile composition packaged in syringes with a useful volume of 5 ml, containing 5 ml of gel), as part of the treatment of the increase in the volume of the buttocks, for aesthetic reasons.
  • the composition according to the invention sterile composition packaged in syringes with a useful volume of 5 ml, containing 5 ml of gel
  • the first follow-up visit was carried out after 1 month post-injection and the second visit after 6 months in order to assess the safety profile and the performance of the composition according to the invention, in the context of the tissue augmentation treatment carried out .
  • composition according to the invention has a very high level of safety, that is to say an excellent tolerance in the subcutaneous tissues of the body,
  • composition according to the invention is effective in the treatment of the increase in the volume of the buttocks.
  • the evaluation of the performance of the treatment by the patient and an independent medical assessor shows that the results obtained at 1 month, as at 6 months, present a significant and harmonious improvement in the volume of the buttocks,
  • the injecting doctor specifies in particular that the new composition according to the invention is easy and very precise to use, with a remarkable capacity of the gel to position itself quickly and to integrate appropriately into the subcutaneous tissues of the body while creating the desired volume.

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Abstract

The present invention relates to a sterile injectable composition in the form of a hydrogel containing cross-linked hyaluronic acid, or one of the salts thereof, a method for preparing the composition, the use of the composition for the body of a human patient in the fields of aesthetics and plastic and reconstructive medicine, and a treatment method involving the injection of said composition into the body of a human patient in the fields of aesthetics and plastic and reconstructive medicine.

Description

COMPOSITION INJECTABLE CONTENANT DE L'ACIDE HYALURONIQUE POUR DES APPLICATIONS  INJECTABLE COMPOSITION CONTAINING HYALURONIC ACID FOR APPLICATIONS
AU NIVEAU DU CORPS  AT THE BODY LEVEL
La présente invention a pour objet : une composition injectable stérile sous forme d'hydrogel contenant de l'acide hyaluronique réticulé, ou l'un de ses sels, The subject of the present invention is: a sterile injectable composition in the form of a hydrogel containing crosslinked hyaluronic acid, or one of its salts,
un procédé de préparation de ladite composition,  a process for the preparation of said composition,
l'utilisation de ladite composition au niveau du corps d'un patient humain dans les domaines de l'esthétique et de la médecine plastique et reconstructive,  the use of said composition in the body of a human patient in the fields of aesthetics and of plastic and reconstructive medicine,
une méthode de traitement par injection de ladite composition au niveau du corps d'un patient humain dans les domaines de l'esthétique et de la médecine plastique et reconstructive.  a method of treatment by injection of said composition into the body of a human patient in the fields of aesthetics and plastic and reconstructive medicine.
L'acide hyaluronique est un polysaccharide formé par la répétition d'une unité disaccharidique composée d'acide D-glucuronique et de N-acétylglucosamine. Sa structure est linéaire et sans spécificité d'espèce. L'acide hyaluronique est largement distribué dans les organismes vivants humains et animaux, dans lesquels il joue de nombreuses fonctions biologiques comme par exemple le contrôle du taux d'hydratation ou le maintien de la viscoélasticité de fluides ou de tissus. On le retrouve notamment en concentration élevée dans le liquide synovial, le corps vitreux de l'œil et dans le derme. Un être humain de 70 kg possède environ 15 g d'acide hyaluronique dont la moitié est contenue dans la peau et cette quantité diminue avec le vieillissement. Hyaluronic acid is a polysaccharide formed by the repetition of a disaccharide unit composed of D-glucuronic acid and N-acetylglucosamine. Its structure is linear and without species specificity. Hyaluronic acid is widely distributed in living human and animal organisms, in which it plays many biological functions such as, for example, controlling the rate of hydration or maintaining the viscoelasticity of fluids or tissues. It is found in particular in high concentration in the synovial fluid, the vitreous body of the eye and in the dermis. A 70 kg human being has approximately 15 g of hyaluronic acid, half of which is contained in the skin and this quantity decreases with aging.
L'acide hyaluronique possède une demi-vie faible dans les organismes vivants (moins de 1 semaine). Hyaluronic acid has a low half-life in living organisms (less than 1 week).
Dans de nombreuses applications en esthétique et en médecine, il est injecté chez les patients sous' sa forme native, c'est-à-dire qu'il n'est pas réticulé et/ou modifié chimiquement. In many applications in aesthetics and medicine, it is injected into patients in its native form, that is to say it is not crosslinked and / or chemically modified.
Pour d'autres applications, il est administré chez les patients sous une forme stabilisée par réticulation. La réticulation permet de considérablement augmenter la durée de vie (encore appelée rémanence) de l'acide hyaluronique in vivo, mais elle permet également de modifier ses propriétés mécaniques et rhéologiques en le rendant notamment plus élastique, ce qui permet alors d'accroître sa capacité à créer du volume une fois injecté dans les tissus souhaités. Ainsi, grâce à cette modification par réticulation, un hydrogel à base d'acide hyaluronique réticulé a par exemple la capacité de combler des rides ou encore de restaurer les volumes du visage sur une période de plusieurs mois. Au cours des 20 dernières années, l'acide hyaluronique réticulé injectable est devenu le traitement de choix pour la correction des volumes du visage en médecine esthétique. En 2016, selon l'American Society for Aesthetic Plastic Surgery (ASAPS), 2.49 millions de procédures à base d'acide hyaluronique réticulé ont été réalisées uniquement aux USA pour des applications au niveau du visage (avec une croissance de +16% par rapport à l'année précédente). For other applications, it is administered to patients in a cross-linked stabilized form. Cross-linking makes it possible to considerably increase the lifespan (also called persistence) of hyaluronic acid in vivo, but it also makes it possible to modify its mechanical and rheological properties by making it in particular more elastic, which then makes it possible to increase its capacity. to create volume once injected into the desired tissues. Thus, thanks to this modification by crosslinking, a hydrogel based on crosslinked hyaluronic acid has for example the capacity to fill in wrinkles or even to restore the volumes of the face over a period of several months. Over the past 20 years, injectable cross-linked hyaluronic acid has become the treatment of choice for correcting facial volumes in aesthetic medicine. In 2016, according to the American Society for Aesthetic Plastic Surgery (ASAPS), 2.49 million procedures based on cross-linked hyaluronic acid were performed only in the USA for applications on the face (with growth of + 16% compared to the previous year).
Dans le cas de la médecine esthétique au niveau du visage (traitement des lèvres, sillons nasogéniens, pommettes, nez, ...), les injections d'acide hyaluronique réticulé sont réalisées par des médecins habilités et formés, et notamment des chirurgiens et des dermatologues. Le produit est administré chez les patients en utilisant des seringues préremplies contenant en général 1 ml d'hydrogel stérile et un traitement requiert la plupart du temps moins de 2 ml pour combler les tissus faciaux visés et ainsi obtenir la correction esthétique souhaitée. In the case of aesthetic medicine on the face (treatment of the lips, nasolabial folds, cheekbones, nose, etc.), injections of crosslinked hyaluronic acid are carried out by authorized and trained doctors, and in particular surgeons and dermatologists. The product is administered to patients using pre-filled syringes usually containing 1 ml of sterile hydrogel and treatment usually requires less than 2 ml to fill the target facial tissue and thus obtain the desired cosmetic correction.
Dans le cas de la médecine esthétique au niveau du corps (traitement des fesses, seins, ...), contrairement au visage et malgré une croissance continue à l'échelle mondiale des besoins des patients pour corriger les défauts cutanés et/ou remodeler les volumes du corps, l'acide hyaluronique réticulé injectable n'a pas réussi à devenir une solution de traitement connue et reconnue au cours des 10 dernières années. En effet, les injections d'acide hyaluronique réticulé au niveau du corps ne sont que très rarement pratiquées par les médecins alors que les chirurgies par pose d'implants ou par transfert de graisse autologue sont de plus en plus plébiscitées. Cette réalité est le signe que les compositions actuellement existantes pour le traitement du corps par injection d'acide hyaluronique réticulé ne sont pas satisfaisantes pour les utilisateurs (= les médecins), mais également pour les patients qui souhaitent bénéficier d'une modification de leur anatomie au niveau du corps. In the case of aesthetic medicine at the level of the body (treatment of the buttocks, breasts, ...), unlike the face and despite a continuous growth on a global scale of the needs of patients to correct skin defects and / or reshape the In body volumes, crosslinked hyaluronic acid for injection has failed to become a known and recognized treatment solution in the past 10 years. In fact, injections of crosslinked hyaluronic acid in the body are only very rarely performed by doctors, while surgeries by implant placement or by autologous fat transfer are more and more popular. This reality is a sign that the currently existing compositions for the treatment of the body by injection of crosslinked hyaluronic acid are not satisfactory for users (= doctors), but also for patients who wish to benefit from a modification of their anatomy. at the body level.
Le but de la présente invention est donc de proposer une nouvelle composition injectable à base d'acide hyaluronique réticulé pour traiter le corps au niveau des tissus sous-cutanés ; composition biorésorbable, temporaire (non permanente), réversible et peu invasive répondant considérablement mieux aux besoins des médecins et de leurs patients par rapport aux compositions injectables à base d'acide hyaluronique réticulé de l'art antérieur. Cette nouvelle composition a pour objectif de permettre l'émergence d'une solution à haut niveau de sécurité, de performance, facile d'utilisation et induisant une forte satisfaction pour les médecins comme pour les patients. Cette nouvelle composition a pour but de pouvoir être utilisée aussi bien pour des applications esthétiques que pour dès applications médicales dans le domaine de la médecine plastique et reconstructive. Ainsi, la présente invention vise précisément à proposer une nouvelle composition sous forme d'hydrogel injectable stérile contenant de l'acide hyaluronique réticulé, ou l'un de ses sels ; composition conditionnée dans une seringue possédant un volume utile égal à 5 ml ± 2 ml. The aim of the present invention is therefore to propose a new injectable composition based on cross-linked hyaluronic acid for treating the body at the level of the subcutaneous tissues; bioresorbable, temporary (non-permanent), reversible and minimally invasive composition which considerably meets the needs of doctors and their patients compared to the injectable compositions based on cross-linked hyaluronic acid of the prior art. This new composition aims to allow the emergence of a solution with a high level of security, performance, easy to use and inducing a high satisfaction for doctors as for patients. The purpose of this new composition is to be able to be used both for aesthetic applications and for medical applications in the field of plastic and reconstructive medicine. Thus, the present invention aims precisely to provide a new composition in the form of a sterile injectable hydrogel containing crosslinked hyaluronic acid, or one of its salts; composition packaged in a syringe having a useful volume equal to 5 ml ± 2 ml.
Cette nouvelle composition spécifiquement conçue pour les besoins du traitement des tissus sous- cutanés du corps, c'est-à-dire pour les parties du corps humain excluant la tête et le visage, possède des caractéristiques qui la différencie significativement des compositions de l'art antérieur. This new composition specifically designed for the needs of the treatment of subcutaneous tissues of the body, that is to say for the parts of the human body excluding the head and the face, has characteristics which significantly differentiate it from the compositions of the prior art.
Une première caractéristique différenciante essentielle est le volume de la seringue utilisée. La composition injectable selon l'invention est conditionnée dans une seringue possédant un volume utile de 5 ml ± 2 ml ; avantageusement de 5 ml. Les compositions de l'art antérieur, elles, sont conditionnées dans des seringues dont le volume utile est supérieur ou égal à 10 ml, et plus précisément de 10 ml, de 20 ml ou de 50 ml. Contrairement au traitement du visage qui nécessite en général moins de 2 ml par session, le traitement du corps nécessite des quantités/doses bien supérieures allant de plusieurs dizaines de millilitres à plusieurs centaines de millilitres. Sur cette base, comme pour les compositions de l'art antérieur, il semble donc pertinent et pratique de conditionner une composition injectable à base d'acide hyaluronique réticulé pour une utilisation corps dans une seringue d'un volume élevé supérieur ou égal à 10 ml. Néanmoins, de manière surprenante et contrairement à ce que ferait l'homme de l'art, la composition de la présente invention est impérativement conditionnée dans une seringue possédant un volume utile significativement inférieur aux solutions actuellement existantes. A first essential distinguishing characteristic is the volume of the syringe used. The injectable composition according to the invention is packaged in a syringe having a useful volume of 5 ml ± 2 ml; advantageously 5 ml. The compositions of the prior art, they are packaged in syringes whose useful volume is greater than or equal to 10 ml, and more precisely 10 ml, 20 ml or 50 ml. Unlike facial treatment, which generally requires less than 2 ml per session, body treatment requires much higher quantities / doses ranging from several tens of milliliters to several hundred milliliters. On this basis, as for the compositions of the prior art, it therefore seems relevant and practical to package an injectable composition based on crosslinked hyaluronic acid for use in the body in a syringe with a high volume greater than or equal to 10 ml. . Nevertheless, surprisingly and contrary to what a person skilled in the art would do, the composition of the present invention is imperatively packaged in a syringe having a useful volume significantly lower than currently existing solutions.
Une deuxième caractéristique différenciante essentielle, combinée à la première relative au volume utile de la seringue de conditionnement, est que l'acide hyaluronique réticulé possède une structure dite « monophasique » (et « cohésive ») et non « biphasique » (et « non cohésive ») comme dans le cas des compositions de l'art antérieur. En effet, les compositions existantes dans le domaine du traitement du corps sont appelées biphasiques et non cohésives car pour les rendre injectables, le fabriquant fragmente l'acide hyaluronique réticulé, c'est-à-dire qu'il génère volontairement des particules d'acide hyaluronique réticulé (de l'ordre de 1000 particules pour 1 ml de composition ; particules possédant un diamètre de plus de 1000 micromètres), ceci afin que le produit puisse s'extruder plus facilement à travers l'aiguille ou la canule utilisée lorsque le médecin pousse sur le piston de la seringue pour administrer le produit chez son patient. Ce type de composition est appelée biphasique car les particules d'acide hyaluronique réticulé (= phase 1) sont présentes dans une phase aqueuse contenant généralement de l'acide hyaluronique non réticulé (= phase 2) ; phase aqueuse viscoélastique qui maintient en suspension les particules réticulées et lubrifie leur passage à travers l'aiguille ou la canule utilisée. Il est important de préciser que ces particules d'acide hyaluronique réticulé possèdent un degré de réticulation particulièrement élevé (degré de modification au sein de la particule souvent supérieur à 15% en mole), une consistance semi-solide, une forte rigidité/élasticité (élasticité G' à 1Hz au sein de la particule souvent supérieure à 1000 Pa), et de ce fait une probabilité significativement plus importante d'être perçue comme un corps étranger par l'organisme (l'acide hyaluronique réticulé biphasique étant d'une part sous forme de particules, ce qui n'est pas le cas de l'acide hyaluronique à son état naturel dans le corps humain, et d'autre part, il est davantage modifié par réticulation et donc beaucoup moins proche de l'acide hyaluronique natif présent dans l'organisme). Ce type de composition est également appelée non cohésive car si on introduit ladite composition dans de l'eau, les particules réticulées se dispersent facilement et rapidement (preuve de leur forte capacité à se dissocier et donc de leur caractéristique non cohésive). De manière surprenante et contrairement aux compositions de l'art antérieur pour un produit dédié au corps, la composition selon l'invention n'est pas constituée d'acide hyaluronique réticulé de structure biphasique et non cohésive (permettant ainsi une diminution de la force d'extrusion nécessaire pour injecter le produit du fait de sa fragmentation en particules). Bien au contraire, la composition selon l'invention possède une structure dite monophasique et cohésive. L'acide hyaluronique réticulé selon l'invention possède alors un degré de réticulation plus faible que celui des particules d'acide hyaluronique réticulé d'un produit dit biphasique, lui permettant ainsi d'être plus proche de l'acide hyaluronique endogène mais aussi d'avoir des propriétés biophysiques plus proches et appropriées aux tissus mous du corps. L'acide hyaluronique réticulé contenu dans la composition selon l'invention jouit donc d'une souplesse/flexibilité importante et il n'est pas transformé en particules d'acide hyaluronique réticulé pour en faciliter l'injection par le médecin : l'acide hyaluronique réticulé monophasique reste donc sous la forme d'une phase dite unique et souple, et cette phase possède une cohésivité significativement plus importante que celle d'un produit dit biphasique (introduit dans l'eau, un tel produit monophasique se dissocie beaucoup moins facilement et rapidement qu'un produit dit biphasique, lui permettant de conserver davantage son unité, sa consistance et sa structure, et donc ses propriétés rhéologiques et mécaniques). Ainsi, la structure monophasique de la composition selon l'invention permet de bénéficier d'un plus haut niveau de sécurité et de propriétés biophysiques plus adaptées aux tissus du corps, et en particulier des tissus sous-cutanés, par rapport aux compositions à base d'acide hyaluronique de l'art antérieur pour des applications au niveau du corps. A second essential differentiating characteristic, combined with the first relating to the useful volume of the conditioning syringe, is that the crosslinked hyaluronic acid has a structure called “monophasic” (and “cohesive”) and not “biphasic” (and “non-cohesive” ”) As in the case of the compositions of the prior art. Indeed, the compositions existing in the field of body treatment are called biphasic and non-cohesive because to make them injectable, the manufacturer fragments the crosslinked hyaluronic acid, that is to say that it voluntarily generates particles of crosslinked hyaluronic acid (of the order of 1000 particles per 1 ml of composition; particles having a diameter of more than 1000 micrometers), this so that the product can be extruded more easily through the needle or the cannula used when the doctor pushes the plunger of the syringe to administer the product to his patient. This type of composition is called biphasic because the particles of crosslinked hyaluronic acid (= phase 1) are present in an aqueous phase generally containing uncrosslinked hyaluronic acid (= phase 2); viscoelastic aqueous phase which keeps the crosslinked particles in suspension and lubricates their passage through the needle or cannula used. It is important to clarify that these crosslinked hyaluronic acid particles have a particularly high degree of crosslinking (degree of modification within the particle often greater than 15 mol%), a semi-solid consistency, high rigidity / elasticity (elasticity G 'at 1 Hz within the particle often greater than 1000 Pa), and therefore a significantly higher probability of being perceived as a foreign body by the organism (biphasic crosslinked hyaluronic acid being on the one hand in the form of particles, which is not the case with hyaluronic acid in its natural state in the human body, and on the other hand, it is more modified by crosslinking and therefore much less close to the native hyaluronic acid present in the body ). This type of composition is also called non-cohesive because if said composition is introduced into water, the crosslinked particles disperse easily and quickly (proof of their high capacity to dissociate and therefore of their non-cohesive characteristic). Surprisingly and unlike the compositions of the prior art for a product dedicated to the body, the composition according to the invention does not consist of crosslinked hyaluronic acid of biphasic and non-cohesive structure (thus allowing a reduction in the strength d extrusion necessary to inject the product due to its fragmentation into particles). On the contrary, the composition according to the invention has a so-called monophasic and cohesive structure. The crosslinked hyaluronic acid according to the invention then has a lower degree of crosslinking than that of the crosslinked hyaluronic acid particles of a so-called biphasic product, thus allowing it to be closer to endogenous hyaluronic acid but also d '' have biophysical properties closer and appropriate to the soft tissues of the body. The crosslinked hyaluronic acid contained in the composition according to the invention therefore enjoys significant suppleness / flexibility and it is not transformed into particles of crosslinked hyaluronic acid to facilitate injection by the doctor: hyaluronic acid cross-linked monophasic therefore remains in the form of a so-called unique and flexible phase, and this phase has a significantly greater cohesiveness than that of a product known as biphasic (introduced into water, such a monophasic product dissociates much less easily and quickly than a product known as biphasic, allowing it to conserve more its unity, its consistency and its structure, and therefore its rheological and mechanical properties). Thus, the monophasic structure of the composition according to the invention makes it possible to benefit from a higher level of security and from biophysical properties more suited to the tissues of the body, and in particular of the subcutaneous tissues, compared to the compositions based hyaluronic acid of the prior art for applications on the body.
Une troisième caractéristique différenciante importante est que la composition selon l'invention peut être extrudée/injectée aisément, et notamment avec une canule ou une aiguille de faible diamètre, ce qui n'est pas possible ou très difficilement possible avec les solutions à base d'acide hyaluronique réticulé de l'art antérieur pour le corps. Ainsi, de manière surprenante compte tenu de sa nature monophasique, la composition selon l'invention peut être injectée dans les tissus sous- cutanés du corps extrêmement facilement avec une canule de 12G à 16G mais elle peut aussi être injectée facilement avec une canule de 18G à 21G. Il est important d'ajouter que la possibilité d'injecter la composition selon l'invention à travers une canule ou aiguille significativement plus fine par rapport aux solutions de l'art antérieur permet également de réduire la douleur du patient lors de l'injection, le risque de contamination lié à la taille de l'incision au niveau du point d'entrée, ainsi que le risque de cicatrices. Cette solution permet aussi de réduire la dose d'anesthésique à administrer au patient lors de l'acte d'injection. A third important differentiating characteristic is that the composition according to the invention can be extruded / injected easily, and in particular with a cannula or needle of small diameter, which is not possible or very difficult to do with solutions based on acid cross-linked hyaluronic from the prior art for the body. Thus, surprisingly given its monophasic nature, the composition according to the invention can be injected into the subcutaneous tissues of the body extremely easily with a 12G to 16G cannula but it can also be easily injected with an 18G cannula at 21G. It is important to add that the possibility of injecting the composition according to the invention through a cannula or needle significantly thinner compared to the solutions of the prior art also makes it possible to reduce the patient's pain during the injection, the risk of contamination related to the size of the incision at the point of entry, as well as the risk of scarring. This solution also makes it possible to reduce the dose of anesthetic to be administered to the patient during the act of injection.
Selon l'invention, la composition contient de l'acide hyaluronique ou l'un de ses sels, et en particulier ses sels acceptables d'un point de vue physiologique comme les sels de sodium, calcium, zinc, potassium, avantageusement le sel de sodium. L'acide hyaluronique peut être d'origine- animale ou obtenu par fermentation bactérienne. Il peut avoir une masse moléculaire de quelques daltons à plusieurs millions de daltons, avantageusement d'environ 0.01 à 5 millions de daltons, encore avantageusement d'environ 0.1 à 3.5 millions de daltons. According to the invention, the composition contains hyaluronic acid or one of its salts, and in particular its physiologically acceptable salts such as the sodium, calcium, zinc, potassium salts, advantageously the salt of sodium. The hyaluronic acid can be of animal origin or obtained by bacterial fermentation. It can have a molecular mass of a few daltons to several million daltons, advantageously from approximately 0.01 to 5 million daltons, still advantageously from approximately 0.1 to 3.5 million daltons.
Selon un aspect de l'invention, la composition peut être à base d'un dérivé de l'acide hyaluronique, c'est-à-dire à base d'une molécule obtenue en modifiant par voie chimique, ou par toute autre voie, la molécule d'acide hyaluronique. According to one aspect of the invention, the composition may be based on a derivative of hyaluronic acid, that is to say based on a molecule obtained by modifying chemically, or by any other route, the hyaluronic acid molecule.
Selon l'invention, la concentration totale en acide hyaluronique, ou l'un de ses sels, est comprise entre 0.001 et 70 mg/ml, entre 0.01 et 50 mg/ml, entre 1 et 40 mg/ml, entre 5 et 35 mg/ml, entre 8 et 33 mg/ml, entre 9 et 30 mg/ml, entre 10 et 29 mg/ml, entre 11 et 28 mg/ml, entre 12 et 27 mg/ml, entre 12 et 26 mg/ml, avantageusement entre 12 et 25 mg/ml. According to the invention, the total concentration of hyaluronic acid, or one of its salts, is between 0.001 and 70 mg / ml, between 0.01 and 50 mg / ml, between 1 and 40 mg / ml, between 5 and 35 mg / ml, between 8 and 33 mg / ml, between 9 and 30 mg / ml, between 10 and 29 mg / ml, between 11 and 28 mg / ml, between 12 and 27 mg / ml, between 12 and 26 mg / ml, advantageously between 12 and 25 mg / ml.
Selon l'invention, l'acide hyaluronique contenu dans la composition est réticulé, totalement ou partiellement, préférentiellement selon les techniques de réticulation décrites dans l'art antérieur. Le ou les agents réticulants qui interviennent dans la réticulation peuvent être identiques ou différents. Ce sont généralement des réticulants bi- ou poly-fonctionnels de différents types et ils peuvent par exemple être sélectionnés parmi la divinylsulfone, les époxy bi- ou poly-fonctionnels, les carbodiimides et le formaldéhyde. On choisit de préférence les agents de la famille des époxy bi- ou poly-fonctionnels et notamment le 1,4-butanedioldiglycidyléther (BDDE), le diépoxy-octane ou le l,2-bis-(2,3-époxypropyl)-2,3-éthylène. On préfère tout particulièrement utiliser le BDDE. Les températures de réticulation sont généralement comprises entre environ 15°C et 60°C et les durées de réticulation sont généralement de plusieurs heures, avantageusement de plus de lh jusqu'à environ 24h. According to the invention, the hyaluronic acid contained in the composition is crosslinked, totally or partially, preferably according to the crosslinking techniques described in the prior art. The crosslinking agent (s) involved in the crosslinking can be identical or different. They are generally bi- or poly-functional crosslinkers of different types and they can for example be selected from divinylsulfone, bi- or poly-functional epoxies, carbodiimides and formaldehyde. Agents of the bi- or poly-functional epoxy family are preferably chosen and in particular 1,4-butanedioldiglycidylether (BDDE), diepoxy-octane or 1,2-bis- (2,3-epoxypropyl) -2 , 3-ethylene. We particularly prefer to use BDDE. Crosslinking temperatures are generally between about 15 ° C and 60 ° C and the durations of crosslinking are generally several hours, advantageously more than 1 hour until approximately 24 hours.
Le degré de réticulation de l'acide hyaluronique, ou l'un de ses sels, dans la composition selon l'invention est avantageusement compris entre 1% et 12%, préférentiellement entre 2% et 10%, préférentiellement entre 3% et 8%. On définit le degré de réticulation comme étant le pourcentage en masse du ratio molaire de l'agent réticulant sur le monomère d'acide hyaluronique. The degree of crosslinking of hyaluronic acid, or one of its salts, in the composition according to the invention is advantageously between 1% and 12%, preferably between 2% and 10%, preferably between 3% and 8% . The degree of crosslinking is defined as being the percentage by mass of the molar ratio of the crosslinking agent to the hyaluronic acid monomer.
Il est important de noter que le réticulant utilisé pour le pontage des chaînes d'acide hyaluronique est une molécule possédant en général un niveau de toxicité non négligeable. Le réticulant résiduel après réticulation (celui n'ayant pas réagi avec l'acide hyaluronique lors de la réticulation) doit être éliminé au maximum au cours de la purification de l'hydrogel (généralement par dialyse dans une solution aqueuse physiologique) de manière à avoir une composition injectable possédant le meilleur niveau de sécurité possible pour le patient. Compte tenu des quantités/doses très importantes de la composition injectable selon l'invention pouvant être administrée dans le corps (quantités/doses considérablement supérieures à celles pouvant être injectées dans le visage), il est impératif que le réticulant résiduel subsistant dans le produit fini soit à un niveau extrêmement faible et donc uniquement sous forme de traces. Ainsi, pour assurer un haut niveau de sécurité de la composition injectable, dans le cas du BDDE cité précédemment, la composition selon l'invention doit impérativement posséder un taux résiduel de ce composé inférieur à 2 ppm, avantageusement inférieur à 1.5 ppm, avantageusement inférieur à 1.0 ppm, avantageusement inférieur à 0.5 ppm, avantageusement inférieur à 0.1 ppm. It is important to note that the crosslinker used for bridging the hyaluronic acid chains is a molecule generally having a non-negligible level of toxicity. The residual crosslinker after crosslinking (that which has not reacted with hyaluronic acid during crosslinking) must be eliminated as much as possible during the purification of the hydrogel (generally by dialysis in a physiological aqueous solution) so as to have an injectable composition having the best possible level of safety for the patient. Given the very large quantities / doses of the injectable composition according to the invention which can be administered into the body (quantities / doses considerably greater than those which can be injected into the face), it is imperative that the residual crosslinking agent remaining in the finished product either at an extremely low level and therefore only in the form of traces. Thus, to ensure a high level of safety of the injectable composition, in the case of the BDDE mentioned above, the composition according to the invention must imperatively have a residual level of this compound of less than 2 ppm, advantageously less than 1.5 ppm, advantageously less at 1.0 ppm, advantageously less than 0.5 ppm, advantageously less than 0.1 ppm.
Selon l'invention, l'acide hyaluronique est totalement ou partiellement réticulé. Ainsi, la composition selon l'invention comprend avantageusement un mélange de plus de 80% en masse d'acide hyaluronique sous la forme réticulée et de moins de 20% en masse d'acide hyaluronique^ sous la forme non réticulée. De manière préférentielle, la fraction massique d'acide hyaluronique sous la forme non réticulée est inférieure ou égale à 15% de la masse totale d'acide hyaluronique dans le produit fini. According to the invention, hyaluronic acid is totally or partially crosslinked. Thus, the composition according to the invention advantageously comprises a mixture of more than 80% by mass of hyaluronic acid in the crosslinked form and of less than 20% by mass of hyaluronic acid ^ in the non-crosslinked form. Preferably, the mass fraction of hyaluronic acid in the non-crosslinked form is less than or equal to 15% of the total mass of hyaluronic acid in the finished product.
Selon l'invention, la composition a pour ingrédient majoritaire l'eau, d'où le qualificatif d'hydrogel ou composition aqueuse pour la nouvelle composition selon l'invention. La masse en eau dans la composition selon l'invention est supérieure à 51% de la masse totale, avantageusement supérieure à 60% de la masse totale, avantageusement supérieure à 70% de la masse totale, avantageusement supérieure à 75% de la masse totale, avantageusement supérieure à 85% de la masse totale, avantageusement supérieure à 95% de la masse totale. Une solution tampon est avantageusement utilisée notamment pour mieux contrôler le pH et l'osmolarité de la formulation tout au long de sa durée de péremption. On peut par exemple citer l'utilisation d'un tampon à base de chlorure de sodium et de sels de phosphates. According to the invention, the majority of the composition is water, hence the qualifier hydrogel or aqueous composition for the new composition according to the invention. The water mass in the composition according to the invention is greater than 51% of the total mass, advantageously greater than 60% of the total mass, advantageously greater than 70% of the total mass, advantageously greater than 75% of the total mass , advantageously greater than 85% of the total mass, advantageously greater than 95% of the total mass. A buffer solution is advantageously used in particular to better control the pH and the osmolarity of the formulation throughout its shelf life. We can for example cite the use of a buffer based on sodium chloride and phosphate salts.
Selon l'invention, la composition injectable stérile possède avantageusement une osmolarité physiologique, c'est-à-dire une osmolarité comprise entre 200 et 400 mOsm/kg, et un pH compris entre 6.0 et 7.9. According to the invention, the sterile injectable composition advantageously has a physiological osmolarity, that is to say an osmolarity of between 200 and 400 mOsm / kg, and a pH of between 6.0 and 7.9.
Selon l'invention, la composition injectable stérile peut contenir un anesthésiant local comme le chlorhydrate de lidocaïne ou tout autre composé permettant de limiter la douleur du patient lors de l'administration du produit chez le patient. According to the invention, the sterile injectable composition may contain a local anesthetic such as lidocaine hydrochloride or any other compound making it possible to limit the patient's pain during the administration of the product to the patient.
Selon l'invention, la composition est stérile et elle est avantageusement stérilisée à la chaleur, préférentiellement à la chaleur humide (également appelée autoclavage à la vapeur). According to the invention, the composition is sterile and it is advantageously sterilized with heat, preferably with moist heat (also called steam autoclaving).
De manière préférée, la stérilisation à la chaleur humide est effectuée à une température supérieure à 100°C, avantageusement supérieure à 110°C, avantageusement supérieure à 120°C. De manière générale, la durée de stérilisation peut aller de quelques secondes à plusieurs minutes. On peut citer par exemple les cycles de stérilisation à la chaleur humide suivants : 121°C pendant 20 minutes ou 125°C pendant 7 minutes ou 127°C pendant 4 minutes ou encore 130°C pendant 3 minutes. Preferably, the moist heat sterilization is carried out at a temperature above 100 ° C, advantageously above 110 ° C, advantageously above 120 ° C. In general, the sterilization time can range from a few seconds to several minutes. Examples include the following moist heat sterilization cycles: 121 ° C for 20 minutes or 125 ° C for 7 minutes or 127 ° C for 4 minutes or 130 ° C for 3 minutes.
Il est important de noter que la stérilisation à la chaleur est avantageusement sélectionnée car elle octroie un très haut niveau de stérilité à la composition choisie, ce qui permet alors de viser un haut niveau de sécurité pour le patient traité. It is important to note that heat sterilization is advantageously selected because it grants a very high level of sterility to the chosen composition, which then makes it possible to aim for a high level of safety for the treated patient.
Selon l'invention, la composition injectable est conditionnée dans une seringue possédant un volume utile égal à 5 ml ± 2 ml. En d'autres termes, le volume utile de la seringue utilisée est compris entre 3.0 ml et 7.0 ml. Avantageusement, la composition selon l'invention est conditionnée dans une seringue possédant un volume utile de 5 ml. Cette seringue peut être en matériau plastique ou en matériau verre, préférentiellement en matériau plastique et plus précisément en matériau Cyclo-Olefin-Copolymer (COC) ou Cyclo-Olefin-Polymer (COP). Cette seringue est avantageusement constituée d'un luer-lock intégré au corps de la seringue, c'est-à-dire directement moulé avec le corps de la seringue, limitant ainsi le risque de rupture du luer-lock. La seringue présente un revêtement sur ses parois internes (préférentiellement un siliconage), ceci facilitant le glissement du joint de piston et réduisant ainsi les forces d'extrusion de la composition. La seringue est équipée d'une tige de piston et d'un appui doigt, fabriqués à partir de matières plastiques (pour faciliter la rigidité et la stabilité lors de l'injection) permettant d'améliorer le confort du médecin et la précision de son injection. La seringue est également équipée d'un joint de piston et d'un bouchon en matière plastique élastomère, permettant de conditionner de manière hermétique le produit, notamment pendant le processus de stérilisation et le stockage de la composition durant sa durée de péremption. According to the invention, the injectable composition is packaged in a syringe having a useful volume equal to 5 ml ± 2 ml. In other words, the useful volume of the syringe used is between 3.0 ml and 7.0 ml. Advantageously, the composition according to the invention is packaged in a syringe having a useful volume of 5 ml. This syringe can be made of plastic material or glass material, preferably plastic material and more precisely Cyclo-Olefin-Copolymer (COC) or Cyclo-Olefin-Polymer (COP) material. This syringe advantageously consists of a luer-lock integrated into the body of the syringe, that is to say directly molded with the body of the syringe, thus limiting the risk of rupture of the luer-lock. The syringe has a coating on its internal walls (preferably siliconization), this facilitating the sliding of the piston seal and thus reducing the extrusion forces of the composition. The syringe is equipped with a plunger rod and a finger support, made from plastic materials (to facilitate rigidity and stability during the injection) to improve the doctor's comfort and the precision of his injection. The syringe is also equipped with a plunger seal and an elastomeric plastic stopper, allowing the product to be hermetically sealed, especially during the sterilization process and the storage of the composition during its expiration period.
Selon l'invention, la composition injectable possède un volume de gel à base d'acide hyaluronique réticulé compris entre 3 ml et 7 ml dans la seringue. Ce volume de gel est avantageusement égal à 5 ml. According to the invention, the injectable composition has a volume of gel based on cross-linked hyaluronic acid of between 3 ml and 7 ml in the syringe. This gel volume is advantageously equal to 5 ml.
Selon l'invention, la composition stérile est administrée chez le patient par injection à travers une canule ou une aiguille. Le diamètre de la canule est avantageusement compris entre 18G et 21G et celui de l'aiguille entre 21G et 25G. La force d'extrusion (en Newtons N) requise pour injecter le gel à travers la canule ou l'aiguille, à la vitesse de 13 mm/min, est avantageusement compris entre 5 N et 40 N, avantageusement entre 10 N et 30 N. According to the invention, the sterile composition is administered to the patient by injection through a cannula or a needle. The diameter of the cannula is advantageously between 18G and 21G and that of the needle between 21G and 25G. The extrusion force (in Newtons N) required to inject the gel through the cannula or the needle, at a speed of 13 mm / min, is advantageously between 5 N and 40 N, advantageously between 10 N and 30 N .
Selon l'invention, la composition stérile injectable à base d'acide hyaluronique réticulé possède une élasticité G' à 1 Hz (et à 1% de déformation) avantageusement comprise entre 50 Pa et 450 Pa, préférentiellement entre 60 Pa et 300 Pa, préférentiellement entre 70 Pa et 250 Pa. Les propriétés viscoélastiques d'un gel à base d'acide hyaluronique sont effectivement essentielles pour la sécurité et l'efficacité produit que ce soit pour des utilisations en esthétique ou en médecine plastique et reconstructive. Dans le cas de la présente invention, la composition injectable stérile de structure monophasique possède avantageusement une élasticité G' à 1 Hz : According to the invention, the sterile injectable composition based on crosslinked hyaluronic acid has an elasticity G 'at 1 Hz (and at 1% deformation) advantageously between 50 Pa and 450 Pa, preferably between 60 Pa and 300 Pa, preferably between 70 Pa and 250 Pa. The viscoelastic properties of a gel based on hyaluronic acid are effectively essential for product safety and efficacy, whether for uses in aesthetics or in plastic and reconstructive medicine. In the case of the present invention, the sterile injectable composition of monophasic structure advantageously has an elasticity G 'at 1 Hz:
- inférieure à 450 Pa, car pour une élasticité du produit supérieure à cette valeur, les tissus de la zone traitée deviennent trop rigides/durs et cela implique un ressenti désagréable et non naturel lors de la palpation ou des mouvements de la zone traitée, - less than 450 Pa, because for an elasticity of the product greater than this value, the tissues of the treated area become too rigid / hard and this implies an unpleasant and unnatural feeling during palpation or movements of the treated area,
- supérieure à 50 Pa, car pour une élasticité inférieure à cette valeur, le produit n'ayant pas suffisamment de résistance à l'étalement, il s'étale et diffuse trop dans les tissus de la zone traitée et il n'est ainsi pas suffisamment en mesure de créer du volume. - greater than 50 Pa, because for an elasticity less than this value, the product not having sufficient resistance to spreading, it spreads and diffuses too much into the tissues of the treated area and it is therefore not sufficiently capable of creating volume.
Selon l'invention, la composition est stable à la température ambiante et sa durée de péremption peut donc atteindre plus de 24 mois dans ces conditions. According to the invention, the composition is stable at room temperature and its shelf life can therefore reach more than 24 months under these conditions.
Selon l'invention, la biocompatibilité de la composition est conforme à la norme ISO 10993. La structure monophasique de la composition, combinée à ses propriétés rhéologiques adaptées et à sa très haute pureté, justifie en grande partie l'excellente tolérance de l'hydrogel dans les tissus sous-cutanés du corps, sur le long terme, et ceci même si l'hydrogel est injecté en grande quantité dans la zone traitée. According to the invention, the biocompatibility of the composition conforms to standard ISO 10993. The monophasic structure of the composition, combined with its suitable rheological properties and its very high purity, largely justifies the excellent tolerance of the hydrogel. in the tissues subcutaneous of the body, in the long term, even if the hydrogel is injected in large quantities in the treated area.
Selon l'invention, la composition injectable permet d'obtenir des bénéfices cliniques au niveau de la zone du corps traitée sur une période moyenne pouvant aller de 6 mois à 24 mois, que ce soit pour des applications esthétiques, ou pour des applications thérapeutiques. According to the invention, the injectable composition makes it possible to obtain clinical benefits in the area of the body treated over an average period which can range from 6 months to 24 months, whether for aesthetic applications or for therapeutic applications.
Selon un aspect de l'invention, la composition selon l'invention contient au maximum 45% en masse, avantageusement au maximum 30 % en masse, avantageusement au maximum 20% en masse, avantageusement au maximum 10% en masse, avantageusement au maximum 5% en masse, avantageusement au maximum 2.5% en masse, avantageusement au maximum 1% en masse, d'un ou plusieurs composés autres que l'eau et l'acide hyaluronique, ou l'un de ses sels. According to one aspect of the invention, the composition according to the invention contains at most 45% by mass, advantageously at most 30% by mass, advantageously at most 20% by mass, advantageously at most 10% by mass, advantageously at most 5 % by mass, advantageously at most 2.5% by mass, advantageously at most 1% by mass, of one or more compounds other than water and hyaluronic acid, or one of its salts.
Selon un aspect de l'invention, la composition selon l'invention contient une ou plusieurs substances actives d'origine naturelle ou synthétique à action pharmacologique ou non, comme par exemple les antioxydants, les anti-inflammatoires, les antiseptiques, les antibactériens, les antifongiques, les anticancéreux, les protéines, les hormones, les acides aminés, les acides gras, les lipides biologiquement acceptables, seuls ou en combinaison. Ces substances actives sont soit dispersées dans l'hydrogel, soit greffées à un ou plusieurs des polymères de l'hydrogel, soit contenues/encapsulées dans des liposomes/niosomes dispersés dans l'hydrogel, soit contenues/encapsulées dans un autre matériau lui-même dispersé au sein de l'hydrogel. According to one aspect of the invention, the composition according to the invention contains one or more active substances of natural or synthetic origin with or without pharmacological action, such as, for example, antioxidants, anti-inflammatories, antiseptics, antibacterials, antifungals, anticancer drugs, proteins, hormones, amino acids, fatty acids, biologically acceptable lipids, alone or in combination. These active substances are either dispersed in the hydrogel, or grafted to one or more of the hydrogel polymers, either contained / encapsulated in liposomes / niosomes dispersed in the hydrogel, or contained / encapsulated in another material itself dispersed within the hydrogel.
Selon un aspect de l'invention, la composition selon l'invention contient un ou plusieurs composés d'origine biologique comme des cellules, des plaquettes enrichies, des gènes, des fragments d'ADN ou des facteurs de croissance. Ces composés sont préférentiellement dispersés dans l'hydrogel, mais ils peuvent également être greffés à un ou plusieurs des polymères de l'hydrogel ou contenus/encapsulés dans des liposomes/niosomes dispersés dans l'hydrogel ou contenus/encapsulés dans un autre matériau lui-même dispersé au sein de l'hydrogel. According to one aspect of the invention, the composition according to the invention contains one or more compounds of biological origin such as cells, enriched platelets, genes, DNA fragments or growth factors. These compounds are preferably dispersed in the hydrogel, but they can also be grafted to one or more of the hydrogel polymers or contained / encapsulated in liposomes / niosomes dispersed in the hydrogel or contained / encapsulated in another material itself. even dispersed within the hydrogel.
Selon un aspect de l'invention, la composition selon l'invention contient des polymères qui sont dispersés au sein de la matrice réticulée de l'hydrogel. On peut citer par exemple les polymères de la famille des polysaccharides, les polyesters, les polyanhydrides, les polyphosphazenes, les poly-e- caprolactones, la cellulose et ses dérivés, les acides polylactiques et leurs dérivés, les acides polyvinyliques, les polyacrylamides, la N-vinyl pyrrolidone et les polymères acryliques et dérivés biologiquement acceptables. Selon un aspect de l'invention, la composition selon l'invention contient des substances minérales qui sont dispersées au sein de la matrice réticulée de l'hydrogel. On peut citer par exemple l'hydroxyapatite ou les phosphates tricalciques comme le b tricalcium phosphate. According to one aspect of the invention, the composition according to the invention contains polymers which are dispersed within the crosslinked matrix of the hydrogel. Mention may be made, for example, of polymers of the polysaccharide family, polyesters, polyanhydrides, polyphosphazenes, poly-e-caprolactones, cellulose and its derivatives, polylactic acids and their derivatives, polyvinyl acids, polyacrylamides, N-vinyl pyrrolidone and biologically acceptable acrylic polymers and derivatives. According to one aspect of the invention, the composition according to the invention contains mineral substances which are dispersed within the crosslinked matrix of the hydrogel. Mention may be made, for example, of hydroxyapatite or tricalcium phosphates such as b tricalcium phosphate.
Selon un aspect de l'invention, la composition selon l'invention est mélangée avec une ou plusieurs autres substances, préférentiellement stériles, susceptibles d'apporter un bénéfice à l'organisme, juste avant son administration chez le patient. Le mélange est alors effectué par l'utilisateur final, c'est-à-dire par le médecin, selon une méthode appropriée utilisant un ou plusieurs dispositifs de mélange permettant de réaliser un mélange satisfaisant et de conserver la stérilité. According to one aspect of the invention, the composition according to the invention is mixed with one or more other substances, preferably sterile, capable of bringing a benefit to the body, just before its administration in the patient. The mixing is then carried out by the end user, that is to say by the doctor, according to an appropriate method using one or more mixing devices making it possible to produce a satisfactory mixture and to maintain sterility.
La nouvelle composition injectable stérile divulguée dans la présente invention a pour objectif de faire naître une nouvelle solution peu invasive, c'est-à-dire non chirurgicale (et n'impliquant pas l'utilisation d'un bloc opératoire), pour le traitement du corps par injection au niveau des tissus sous-cutanés : The new sterile injectable composition disclosed in the present invention aims to give birth to a new minimally invasive solution, that is to say non-surgical (and not involving the use of an operating theater), for treatment of the body by injection into the subcutaneous tissues:
- alternative et/ou complémentaire aux solutions chirurgicales actuelles de pose d'implants ou de transfert de graisse, et, - alternative and / or complementary to current surgical solutions for implant placement or fat transfer, and,
- possédant un niveau de sécurité, une performance clinique et une satisfaction pour les médecins et les patients significativement plus importants que pour les compositions existantes à base d'acide hyaluronique réticulé. - having a significantly higher level of safety, clinical performance and satisfaction for doctors and patients than for existing compositions based on cross-linked hyaluronic acid.
Ainsi, de par ses caractéristiques nouvelles et uniques, la composition injectable selon l'invention possède les avantages considérables suivants par rapport aux compositions à base d'acide hyaluronique réticulé de l'art antérieur pour traiter les tissus sous-cutanés du corps d'un patient : Thus, by its new and unique characteristics, the injectable composition according to the invention has the following considerable advantages compared to the compositions based on cross-linked hyaluronic acid of the prior art for treating the subcutaneous tissues of the body of a patient:
- la composition injectable selon l'invention est facilement injectable à travers une canule ou une aiguille, ce qui permet alors de pouvoir utiliser une canule ou aiguille de plus petit diamètre. Ainsi, alors que les compositions de l'art antérieur sont généralement administrées avec une large canule de 12G, la présente composition, compte tenu de ses caractéristiques, peut être injectée avec une canule significativement plus fine de 18G à 21G. De ce fait, le diamètre de l'incision est considérablement réduit, ce qui permet alors de procéder à l'acte d'injection en cabinet de ville (comme dans le cas du traitement du visage) et non en bloc opératoire, et sans anesthésie générale. La procédure est alors considérablement moins longue, moins risquée, moins complexe et moins coûteuse, - The injectable composition according to the invention is easily injectable through a cannula or a needle, which then makes it possible to be able to use a cannula or needle of smaller diameter. Thus, while the compositions of the prior art are generally administered with a large 12G cannula, the present composition, given its characteristics, can be injected with a significantly finer cannula from 18G to 21G. As a result, the diameter of the incision is considerably reduced, which then makes it possible to proceed with the act of injection in a city office (as in the case of facial treatment) and not in the operating room, and without anesthesia general. The procedure is then considerably shorter, less risky, less complex and less costly,
- la possibilité d'injecter la composition selon l'invention à travers une canule ou aiguille significativement plus fine par rapport aux solutions de l'art antérieur permet de réduire la douleur du patient à l'injection, le risque de contamination lié à la taille de l'incision au niveau du point d'entrée ainsi que le risque de cicatrices, the possibility of injecting the composition according to the invention through a cannula or needle significantly thinner compared to the solutions of the prior art makes it possible to reduce the pain of the patient at the injection, the risk of contamination linked to the size of the incision at the point of entry as well as the risk of scars,
- la composition selon l'invention est très ergonomique du fait d'une seringue plus petite, permettant alors au médecin d'être beaucoup plus précis dans son traitement lors de l'injection du produit mais aussi d'avoir une fatigue moins importante de la main qui procède à l'acte d'injection, - The composition according to the invention is very ergonomic due to a smaller syringe, then allowing the doctor to be much more precise in his treatment during the injection of the product but also to have less fatigue of the hand that performs the act of injection,
- la composition selon l'invention est moins impressionnante pour le patient (= seringue moins grande et canule de diamètre considérablement plus petit), rendant l'expérience du traitement plus agréable pour le patient qui n'est pas sous anesthésie générale et qui peut donc interagir avec son médecin pendant l'acte pour viser une correction optimale de la zone souhaitée, - the composition according to the invention is less impressive for the patient (= smaller syringe and cannula of considerably smaller diameter), making the treatment experience more pleasant for the patient who is not under general anesthesia and who can therefore interact with your doctor during the procedure to aim for optimal correction of the desired area,
- les volumes injectés pouvant être très importants et nécessitant plus d'une seringue pour une session de traitement, l'excellente ergonomie de la composition selon l'invention (taille de seringue davantage adaptée à la main du médecin par rapport à une plus grosse seringue de 10 ml, 20 ml ou 50 ml) permet de substituer facilement et rapidement la seringue vide par une nouvelle seringue pleine, tout en gardant la canule/aiguille dans la zone du corps qui est en train d'être traitée, - The volumes injected can be very large and require more than one syringe for a treatment session, the excellent ergonomics of the composition according to the invention (syringe size more suited to the doctor's hand compared to a larger syringe 10 ml, 20 ml or 50 ml) allows you to easily and quickly replace the empty syringe with a new full syringe, while keeping the cannula / needle in the area of the body that is being treated,
- la composition selon l'invention permet de significativement réduire les risques de surdosage du fait du plus faible volume d'hydrogel contenu dans la seringue. En effet, dans le cas des compositions de l'art antérieur à base d'acide hyaluronique réticulé, les volumes de seringue importants de 10 ml, 20 ml ou 50 ml peuvent inciter le médecin à utiliser l'intégralité de la seringue chez le patient traité alors que cela n'est pas nécessaire. De ce fait, dans le cas de la composition selon l'invention, le volume ajusté de 5 ml ± 2 ml permet de traiter le patient de manière plus raisonnée et proportionnée, - The composition according to the invention significantly reduces the risk of overdose due to the lower volume of hydrogel contained in the syringe. Indeed, in the case of the compositions of the prior art based on crosslinked hyaluronic acid, the large syringe volumes of 10 ml, 20 ml or 50 ml may encourage the doctor to use the entire syringe in the patient. treated when it is not necessary. Therefore, in the case of the composition according to the invention, the adjusted volume of 5 ml ± 2 ml makes it possible to treat the patient in a more reasoned and proportioned manner,
- la composition selon l'invention permet également de significativement réduire le risque de réutilisation d'une seringue partiellement utilisée pour une nouvelle application ultérieure, ceci compte tenu du plus faible volume de composition qu'elle contient. En effet, dans le cas des compositions de l'art antérieur, les volumes de seringue importants de 10 ml, 20 ml ou 50 ml peuvent inciter le médecin à n'utiliser qu'une fraction de la composition et conserver le reste du produit (ayant perdu sa stérilité) pour une utilisation ultérieure. Ces pratiques peuvent engendrer des risques graves de contamination et d'infection pour le patient. De ce fait, dans le cas de la composition selon l'invention, le volume de 5 ml ± 2 ml est ajusté au traitement des zones nécessitant des volumes faibles, ce qui permet alors l'utilisation complète de la composition lors d'une seule session de traitement, et n'incite donc pas le médecin à conserver une seringue partiellement utilisée pour une application ultérieure, - la structure monophasique (et donc cohésive) de la composition selon l'invention permet d'avoir un produit qui se distribue et se positionne significativement mieux dans les tissus sous-cutanés par rapport aux compositions biphasiques de l'art antérieur, permettant ainsi d'obtenir un résultat clinique plus homogène et naturel (souplesse des tissus et aspect de surface lisse), respectant ainsi davantage la biomécanique des tissus de la zone traitée, the composition according to the invention also makes it possible to significantly reduce the risk of re-using a syringe partially used for a new subsequent application, this taking into account the lower volume of composition that it contains. In fact, in the case of the compositions of the prior art, the large syringe volumes of 10 ml, 20 ml or 50 ml can encourage the doctor to use only a fraction of the composition and keep the rest of the product ( having lost its sterility) for later use. These practices can create serious risks of contamination and infection for the patient. Therefore, in the case of the composition according to the invention, the volume of 5 ml ± 2 ml is adjusted to the treatment of the areas requiring low volumes, which then allows the complete use of the composition in a single treatment session, and therefore does not encourage the doctor to keep a partially used syringe for later application, - The monophasic (and therefore cohesive) structure of the composition according to the invention makes it possible to have a product which distributes and positions itself significantly better in the subcutaneous tissues compared to the biphasic compositions of the prior art, thus allowing d '' obtain a more homogeneous and natural clinical result (tissue flexibility and smooth surface appearance), thus more respecting the biomechanics of the tissues in the treated area,
- la structure monophasique, combinée à des propriétés rhéologiques spécifiques de la composition selon l'invention, permet également d'avoir un produit avec un plus haut niveau de sécurité qui crée davantage de volume car le produit se disperse moins (car plus forte cohésivité) lors de l'injection dans les tissus graisseux mais également au cours des mois suivant l'injection du produit (risque de migration considérablement réduit). - the monophasic structure, combined with specific rheological properties of the composition according to the invention, also makes it possible to have a product with a higher level of safety which creates more volume because the product disperses less (because higher cohesiveness) during injection into fatty tissue but also during the months following injection of the product (risk of migration considerably reduced).
D'autre part, au regard des solutions chirurgicales que sont la pose d'implants et le transfert de graisse autologue, largement pratiquées à l'échelle mondiale, cette nouvelle composition injectable permet les avantages suivants : On the other hand, with regard to the surgical solutions that are the placement of implants and the transfer of autologous fat, widely practiced worldwide, this new injectable composition allows the following advantages:
- le médecin n'a pas besoin' de réaliser le traitement dans un bloc opératoire, ni d'utiliser d'anesthésie générale, - the doctor does not need 'to carry out the treatment in an operating room or to use general anesthesia,
- le risque de sécurité est considérablement réduit car pas de chirurgie, d'anesthésie générale, et de cicatrices liées à l'administration du produit, - the safety risk is considerably reduced because no surgery, general anesthesia, and scars linked to the administration of the product,
- l'acte d'injection pour le médecin est significativement moins complexe et moins long à réaliser par rapport à une chirurgie, - the act of injection for the doctor is significantly less complex and less time-consuming compared to surgery,
- le médecin peut réaliser une ou plusieurs retouches pour améliorer les résultats cliniques, suite à la première session d'injection, si cela est nécessaire (en cabinet de ville du médecin et donc pas en bloc opératoire comme dans le cas d'une chirurgie), - the doctor can carry out one or more touch-ups to improve the clinical results, following the first injection session, if necessary (in the doctor's office and therefore not in the operating room as in the case of surgery) ,
- le médecin a la possibilité d'améliorer les résultats d'une chirurgie (implant, transfert de graisse ou autre) en complétant les résultats post-chirurgie (par exemple, correction d'irrégularités ou d'une dépression cutanée) tout en évitant de devoir retourner au bloc opératoire pour subir une nouvelle chirurgie. - the doctor has the possibility of improving the results of a surgery (implant, fat transfer or other) by completing the post-surgery results (for example, correction of irregularities or skin depression) while avoiding having to return to the operating room to have another surgery.
La présente invention concerne, selon un deuxième de ses aspects, un procédé de préparation de la nouvelle composition injectable stérile décrite précédemment. The present invention relates, according to a second of its aspects, to a process for preparing the new sterile injectable composition described above.
Le procédé de préparation de la composition selon l'invention se caractérise par les étapes successives suivantes : a) préparation d'un hydrogel à base d'acide hyaluronique réticulé, ou l'un de ses sels, selon les conditions de l'invention, The process for preparing the composition according to the invention is characterized by the following successive steps: a) preparation of a hydrogel based on cross-linked hyaluronic acid, or one of its salts, according to the conditions of the invention,
b) conditionnement de l'hydrogel en seringues de 5 ml ± 2 ml,  b) packaging of the hydrogel in syringes of 5 ml ± 2 ml,
c) stérilisation.  c) sterilization.
L'étape (a) débute généralement par la mise en solution de l'acide hyaluronique puis par sa réticulation, à l'aide d'un réticulant, et elle se termine généralement par la purification de l'hydrogel obtenu. Step (a) generally begins with the dissolution of the hyaluronic acid and then by its crosslinking, using a crosslinker, and it generally ends with the purification of the hydrogel obtained.
On entend par étape de réticulation de l'acide hyaluronique, l'étape permettant de ponter les chaînes d'acide hyaluronique les unes aux autres par des liaisons covalentes. De manière générale, l'étape de réticulation de l'acide hyaluronique commence lorsque le réticulant est mis en contact avec l'acide hyaluronique et se termine lorsque l'homme de l'art considère que la cinétique de réaction de pontage des chaînes d'acide hyaluronique par le réticulant a atteint un niveau négligeable. The term “crosslinking step of hyaluronic acid” is understood to mean the step making it possible to bridge the chains of hyaluronic acid to one another by covalent bonds. In general, the crosslinking step of hyaluronic acid begins when the crosslinker is brought into contact with hyaluronic acid and ends when a person skilled in the art considers that the reaction kinetics of bridging chains hyaluronic acid by the crosslinker has reached a negligible level.
La purification de l'hydrogel, elle, permet de retirer les molécules indésirables du gel préparé et en particulier les résidus de réticulant, suite à la réticulation. Cette purification est effectuée selon les techniques bien connues par l'homme de l'art comme par exemple par bains de dialyse, par lavage par flux d'eau continu ou par précipitation. Purification of the hydrogel, on the other hand, makes it possible to remove the undesirable molecules from the prepared gel and in particular the crosslinker residues, following crosslinking. This purification is carried out according to techniques well known to those skilled in the art, for example by dialysis baths, by washing with a continuous flow of water or by precipitation.
La préparation d'un hydrogel à base d'acide hyaluronique réticulé est effectuée avantageusement selon les méthodes décrites dans l'art antérieur. The preparation of a hydrogel based on crosslinked hyaluronic acid is advantageously carried out according to the methods described in the prior art.
L'étape (b) consiste à remplir l'hydrogel préparé au cours de l'étape (a) dans des seringues de 5 ml ± 2 ml. L'opération de remplissage en seringues peut être effectuée par méthode manuelle ou à l'aide d'une machine de remplissage semi-automatique ou automatique. Step (b) consists in filling the hydrogel prepared during step (a) in syringes of 5 ml ± 2 ml. The syringe filling operation can be carried out by manual method or using a semi-automatic or automatic filling machine.
L'étape (c) consiste à stériliser la composition par les techniques bien connues par l'homme de l'art; la stérilisation étant avantageusement réalisée à la chaleur humide par autoclavage. Step (c) consists in sterilizing the composition by techniques well known to those skilled in the art; sterilization being advantageously carried out with moist heat by autoclaving.
Un procédé avantageux selon l'invention pour la fabrication d'une composition aqueuse stérile injectable selon l'invention comprend au moins les étapes suivantes : préparation d'une solution aqueuse d'acide hyaluronique, An advantageous process according to the invention for the manufacture of a sterile aqueous injectable composition according to the invention comprises at least the following steps: preparation of an aqueous solution of hyaluronic acid,
réticulation de l'acide hyaluronique,  crosslinking of hyaluronic acid,
purification de l'hydrogel, par exemple par dialyse dans une solution physiologique, conditionnement en seringues de 5 ml ± 2 ml, stérilisation. purification of the hydrogel, for example by dialysis in a physiological solution, packaging in syringes of 5 ml ± 2 ml, sterilization.
La présente invention concerne, selon un troisième de ses aspects, l'utilisation chez l'humain, au niveau du corps exclusivement (ceci excluant donc la tête le visage), de la nouvelle composition aqueuse stérile injectable décrite précédemment, pour des applications esthétiques ou thérapeutiques en médecine plastique et reconstructive. The present invention relates, according to a third of its aspects, to the use in humans, at the level of the body exclusively (this therefore excluding the head and the face), of the new sterile aqueous injectable composition described above, for aesthetic applications or therapeutics in plastic and reconstructive medicine.
La composition selon l'invention est utilisée au niveau du corps par injection profonde avec une canule ou une aiguille dans les tissus, et en particulier dans les tissus sous-cutanés. Dans le but d'obtenir un résultat clinique optimal, il est recommandé que l'injection soit réalisée dans une zone où l'épaisseur des tissus (incluant les tissus graisseux sous-cutanés) soit suffisante. Il est important de préciser que l'administration de la composition selon l'invention est interdite dans les vaisseaux sanguins et dans les tissus intra-articulaires et elle n'est pas recommandée dans les tissus musculaires ou dans le cadre d'injections trop superficielles à la surface du corps. The composition according to the invention is used at the level of the body by deep injection with a cannula or a needle in the tissues, and in particular in the subcutaneous tissues. In order to obtain an optimal clinical result, it is recommended that the injection be carried out in an area where the thickness of the tissues (including the subcutaneous fatty tissues) is sufficient. It is important to specify that the administration of the composition according to the invention is prohibited in the blood vessels and in the intra-articular tissues and it is not recommended in the muscular tissues or in the context of injections which are too superficial to the surface of the body.
De manière générale, la composition selon l'invention est utilisée au niveau du corps pour : combler, augmenter ou restaurer des volumes, In general, the composition according to the invention is used on the body to: fill, increase or restore volumes,
améliorer les propriétés viscoélastiques et biomécaniques des tissus comme leur élasticité, améliorer des aspects de surface,  improve the viscoelastic and biomechanical properties of fabrics such as their elasticity, improve surface aspects,
stimuler ou favoriser la régénération des tissus,  stimulate or promote tissue regeneration,
hydrater et protéger des tissus,  moisturize and protect tissues,
générer des espaces au sein de certains tissus, favorisant ainsi leur fonctionnement optimal, délivrer des substances susceptibles d'apporter un bénéfice à l'organisme et notamment des substances actives et/ou des biologiques.  generate spaces within certain tissues, thus promoting their optimal functioning, deliver substances capable of bringing a benefit to the organism and in particular active substances and / or biologicals.
La composition selon l'invention est particulièrement adaptée : The composition according to the invention is particularly suitable:
- au traitement des surfaces du corps comme par exemple pour améliorer des irrégularités de surface, corriger des dépressions cutanées ou améliorer la qualité des tissus et notamment leur élasticité et leur texture (souplesse, fermeté), - to the treatment of body surfaces such as for example to improve surface irregularities, correct skin depressions or improve the quality of tissues and in particular their elasticity and texture (flexibility, firmness),
- à la restauration/augmentation des volumes du corps comme par exemple pour augmenter le volume au niveau des fesses, des seins, des mollets, de la poitrine, du décolleté, du dos, des cuisses, des jambes, du ventre, des hanches, des épaules, des bras, des avant-bras, des mains, des pieds et des organes génitaux. La composition selon l'invention peut être utilisée dans le cadre d'un traitement esthétique du corps, par exemple pour corriger les effets liés au vieillissement ou encore pour augmenter des zones du corps qui le nécessitent. - to restore / increase body volumes, for example to increase the volume in the buttocks, breasts, calves, chest, décolleté, back, thighs, legs, belly, hips, shoulders, arms, forearms, hands, feet and genitals. The composition according to the invention can be used in the context of an aesthetic treatment of the body, for example to correct the effects linked to aging or also to increase areas of the body which require it.
La composition peut être utilisée dans le cadre d'un traitement thérapeutique du corps en médecine plastique ou reconstructive comme par exemple pour traiter des défauts de structures d'origine congénitale ou médicale (maladie, traumatisme, post-chirurgie, ...). On peut notamment citer le traitement des tissus cicatriciels à la surface du corps, la restauration des volumes corporels chez des patients atteints de maladies comme le VIH, la reconstruction de zones du corps qui ont été traumatisées ou chirurgicalement extraites, la correction de cavités comme par exemple une cavité formée suite à une chirurgie orthopédique de l'épaule, la correction d'imperfections postchirurgie à la surface du corps comme par exemple des irrégularités ou des dépressions cutanées suite à une liposuccion ou un lipofilling. The composition can be used in the context of a therapeutic treatment of the body in plastic or reconstructive medicine, for example to treat structural defects of congenital or medical origin (illness, trauma, post-surgery, etc.). These include the treatment of scar tissue on the surface of the body, the restoration of body volumes in patients with diseases such as HIV, the reconstruction of areas of the body that have been traumatized or surgically extracted, the correction of cavities such as example a cavity formed following an orthopedic surgery of the shoulder, the correction of post-surgical imperfections on the surface of the body such as for example irregularities or cutaneous depressions following a liposuction or a lipofilling.
La présente invention concerne, selon un quatrième de ses aspects, une méthode de traitement à but esthétique ou thérapeutique chez l'humain, au niveau du corps exclusivement (ceci excluant donc la tête et le visage), par injection profonde avec une canule ou une aiguille dans les tissus sous- cutanés, de la composition selon l'invention décrite précédemment pour : The present invention relates, according to a fourth of its aspects, to a method of treatment for aesthetic or therapeutic purposes in humans, exclusively at the level of the body (this therefore excluding the head and the face), by deep injection with a cannula or a needle in the subcutaneous tissues, of the composition according to the invention described above for:
- traiter des surfaces du corps comme par exemple pour améliorer des irrégularités de surface, corriger des dépressions cutanées ou améliorer la qualité des tissus et notamment leur élasticité et leur texture (souplesse, fermeté), - treating surfaces of the body such as for example to improve surface irregularities, correct skin depressions or improve the quality of the tissues and in particular their elasticity and texture (flexibility, firmness),
- restaurer/corriger des volumes du corps comme par exemple pour augmenter le volume au niveau des fesses, des seins, des mollets, de la poitrine, du décolleté, du dos, des cuisses, des jambes, du ventre, des hanches, des épaules, des bras, des avant-bras, des mains, des pieds et des organes génitaux. - restore / correct body volumes such as for example to increase the volume in the buttocks, breasts, calves, chest, cleavage, back, thighs, legs, belly, hips, shoulders , arms, forearms, hands, feet and genitals.
Ainsi, cette invention concerne notamment une méthode thérapeutique ou non thérapeutique pour augmenter, corriger, restaurer ou créer du volume au niveau du corps d'un patient, caractérisée par : Thus, this invention relates in particular to a therapeutic or non-therapeutic method for increasing, correcting, restoring or creating volume in the body of a patient, characterized by:
- l'injection en sous-cutané, dans au moins une zone du corps du patient, d'une quantité nécessaire de la composition aqueuse injectable stérile décrite dans la présente invention, the subcutaneous injection, into at least one area of the patient's body, of a necessary quantity of the sterile injectable aqueous composition described in the present invention,
- la réalisation optionnelle d'une désinfection de la zone à traiter, avant l'injection de la composition aqueuse injectable stérile. - la réalisation optionnelle d'un massage de la zone traitée, après l'injection de la composition aqueuse injectable stérile, pour permettre un positionnement optimal du produit dans les tissus, - The optional realization of a disinfection of the area to be treated, before the injection of the sterile injectable aqueous composition. - optional massage of the treated area, after injection of the sterile injectable aqueous composition, to allow optimal positioning of the product in the tissues,
- la zone à traiter au niveau du corps est sélectionnée dans le groupe comprenant les fesses, les seins, les mollets, la poitrine, le décolleté, le dos, les cuisses, les jambes, le ventre, les hanches, les épaules, les bras, les avant-bras, les mains, les pieds et les organes génitaux. - the area to be treated at the body level is selected from the group comprising the buttocks, breasts, calves, chest, cleavage, back, thighs, legs, stomach, hips, shoulders, arms , forearms, hands, feet and genitals.
La technique d'injection de la composition selon l'invention peut varier en fonction de la zone corporelle à traiter, de la profondeur exacte d'injection dans les tissus sous-cutanés, de la quantité à administrer, et des habitudes et préférences du médecin. The technique for injecting the composition according to the invention may vary depending on the body area to be treated, the exact depth of injection into the subcutaneous tissues, the amount to be administered, and the habits and preferences of the doctor. .
Avant l'injection de la composition selon l'invention, il est recommandé au médecin de faire une désinfection rigoureuse de la zone du corps qu'il souhaite traiter afin d'éviter une contamination de l'hydrogel injecté par des bactéries et/ou autres composés étrangers au corps (par exemple, des traces de produits cosmétiques). Before injecting the composition according to the invention, the doctor is recommended to carry out a rigorous disinfection of the area of the body which he wishes to treat in order to avoid contamination of the hydrogel injected with bacteria and / or other compounds foreign to the body (for example, traces of cosmetic products).
Une anesthésie locale de la zone à traiter, par injection et/ou par application d'un anesthésiant topique, peut être réalisée par le médecin. Local anesthesia of the area to be treated, by injection and / or by application of a topical anesthetic, may be performed by the doctor.
Une canule ou une aiguille est ensuite connectée à la seringue de la composition selon l'invention, en suivant les indications fournies dans la notice d'utilisation. La composition selon l'invention est administrée lentement, de manière régulière et maîtrisée, dans les tissus sous-cutanés de la zone corporelle traitée. Le médecin observe alors avec attention l'augmentation tissulaire induite, mais aussi tout signe indésirable potentiellement généré par l'injection comme une décoloration de la peau ou une douleur trop importante chez le patient, nécessitant alors une action du médecin (comme un arrêt partiel ou total de l'injection en cours). A cannula or needle is then connected to the syringe of the composition according to the invention, following the indications provided in the instructions for use. The composition according to the invention is administered slowly, regularly and under control, into the subcutaneous tissues of the body area treated. The doctor then carefully observes the induced tissue increase, but also any unwanted sign potentially generated by the injection such as discoloration of the skin or too much pain in the patient, requiring action by the doctor (such as a partial stop or total of the injection in progress).
Certaines zones sont traitées en procédant à l'injection de la composition selon l'invention par un seul point d'entrée, alors que d'autres zones sont traitées en réalisant des injections par différents points d'entrée. Certain zones are treated by injecting the composition according to the invention at a single entry point, while other zones are treated by injecting at different entry points.
Lorsque le médecin considère avoir injecté suffisamment de la composition selon l'invention, il lui est recommandé de procéder à un massage doux de la zone traitée afin que l'hydrogel puisse se positionner de la manière la plus appropriée et harmonieuse possible dans les tissus sous-cutanés. When the doctor considers having injected enough of the composition according to the invention, he is recommended to carry out a gentle massage of the treated area so that the hydrogel can be positioned in the most appropriate and harmonious way possible in the tissues under - cutaneous.
Les quantités administrées de la composition selon l'invention peuvent aller de quelques millilitres (comme par exemple dans le cas du traitement d'une cicatrice ou d'une cavité/dépression postchirurgie sur le corps), à plusieurs centaines de millilitres (comme par exemple dans le cas de l'augmentation du volume des fesses ou des seins), en fonction de l'indication exacte visée. En général, un patient ne doit pas recevoir plus de 600 ml de la composition au cours d'une année. The amounts administered of the composition according to the invention can range from a few milliliters (as for example in the case of the treatment of a scar or a post-surgical cavity / depression on the body), to several hundred milliliters (as for example in the case of increase in the volume of the buttocks or breasts), depending on the exact indication intended. In general, a patient should not receive more than 600 ml of the composition in a year.
Le traitement de la zone du corps visée par le médecin peut être réalisé au cours d'une seule session ou au cours de plusieurs sessions d'injection. The treatment of the area of the body targeted by the doctor can be carried out during a single session or during several injection sessions.
Des nouvelles injections (dites « retouches ») de plus faibles volumes par rapport à l'injection initiale peuvent être réalisées au cours du temps par le médecin afin d'optimiser cliniquement le résultat obtenu et/ou pour maintenir l'effet clinique souhaité au fil des mois. New injections (called "touch-ups") of smaller volumes compared to the initial injection can be performed over time by the doctor in order to clinically optimize the result obtained and / or to maintain the desired clinical effect over time. months.
EXEMPLES EXAMPLES
L'invention va maintenant être illustrée, de manière non limitative, par les exemples suivants. The invention will now be illustrated, without limitation, by the following examples.
Le hyaluronate de sodium, le chlorhydrate de lidocaïne et l'ensemble des autres composés utilisés dans les exemples suivants possèdent un haut niveau de pureté. Sodium hyaluronate, lidocaine hydrochloride and all the other compounds used in the following examples have a high level of purity.
La solution de tampon phosphate utilisée possède la composition suivante : 8.5 g de NaCI, 0.041 g de NaH2P04 dihydrate, 0.292 g de Na2HP04dihydrate dans 1 litre d'eau pour préparation injectable. The phosphate buffer solution used has the following composition: 8.5 g of NaCl, 0.041 g of NaH 2 P0 4 dihydrate, 0.292 g of Na 2 HP0 4 dihydrate in 1 liter of water for injection.
Les propriétés rhéologiques (mesure du module élastique G') des gels sont mesurées à 25°C à l'aide d'un rhéomètre à contrainte imposée (TA HR-1) et d'une géométrie cône/plan 4 cm-2° avec un entrefer de 1000 micromètres. The rheological properties (measurement of the elastic modulus G ') of the gels are measured at 25 ° C using a constrained rheometer (TA HR-1) and a cone / plane geometry 4 cm-2 ° with an air gap of 1000 micrometers.
La concentration en BDDE résiduel dans les gels est mesurée par HPLC-MS. The concentration of residual BDDE in the gels is measured by HPLC-MS.
Les forces d'extrusion des gels au travers des canules sont mesurées sur un banc de compression, à une vitesse de 13 mm/min, à l'aide d'un capteur de force 200 N. The extrusion forces of the gels through the cannulas are measured on a compression bench, at a speed of 13 mm / min, using a force sensor 200 N.
Exemple 1 : Préparation des compositions GELlAs, GELIBs et GELICs selon l'invention Example 1: Preparation of the GELlAs, GELIBs and GELICs compositions according to the invention
On pèse 1.27 g d'une poudre de hyaluronate de sodium (NaHA), de masse moléculaire environ égale à 1.9 MDa, avec un taux d'humidité de 6.3%, auxquels on ajoute 8.75 g d'une solution aqueuse de NaOH à 0.25 N. L'hydratation de la poudre dure lhlO, avec une homogénéisation manuelle régulière à la spatule.0.42 g d'une solution de 1,4-butanedioldiglycidyléther (BDDE) dilué au l/5ème dans la soude 0.25 N sont ajoutés au milieu réactionnel, suivi d'une homogénéisation mécanique de 45 minutes avant immersion dans un bain thermostaté à 50°C pendant 3h20. On ajoute une solution de tampon phosphate contenant du HCl dans le réticulat obtenu afin d'obtenir un pH=7.4 et une concentration en acide hyaluronique égale à 50 mg/ml. On laisse le gel gonfler pendant 6h à température ambiante dans cette solution et, à la fin de ce temps, on l'homogénéisé manuellement à la spatule pendant 10 minutes avant de le purifier par dialyse pendant 96h en utilisant une membrane à base de cellulose (seuil de rétention = 10 000 Da) dans une solution de tampon phosphate. On ajoute une solution de tampon phosphate au gel dialysé et on mélange manuellement le gel à la spatule pendant 10 minutes. Soit GEL1 le gel ainsi obtenu. La concentration en acide hyaluronique de GEL1 est de 30 mg/ml. Weigh 1.27 g of a sodium hyaluronate powder (NaHA), of molecular mass approximately equal to 1.9 MDa, with a moisture content of 6.3%, to which 8.75 g of a 0.25 N aqueous NaOH solution are added. . the hydration of the hard powder LHLO with regular manual homogenization to spatule.0.42 g of a solution of 1,4-butanediol diglycidyl ether (BDDE) diluted l / 5 th in 0.25 N sodium hydroxide are added to the reaction medium , followed by mechanical homogenization for 45 minutes before immersion in a thermostatically-controlled bath at 50 ° C for 3.20 hrs. We add a phosphate buffer solution containing HCl in the reticulate obtained in order to obtain a pH = 7.4 and a hyaluronic acid concentration equal to 50 mg / ml. The gel is left to swell for 6 hours at room temperature in this solution and, at the end of this time, it is homogenized manually with a spatula for 10 minutes before being purified by dialysis for 96 hours using a cellulose-based membrane ( retention threshold = 10,000 Da) in a phosphate buffer solution. Add a phosphate buffer solution to the dialyzed gel and mix the gel manually with a spatula for 10 minutes. Let GEL1 be the gel thus obtained. The hyaluronic acid concentration of GEL1 is 30 mg / ml.
Dans 28.85 g de gel GEL1, on ajoute une poudre de chlorhydrate de lidocaïne et on mélange manuellement le gel à la spatule pendant 10 minutes. On ajoute une solution d'acide hyaluronique non réticulée (masse moléculaire environ égale à 1.5 MDa) à 35 mg/ml et on mélange manuellement le gel à la spatule pendant 10 minutes. On ajuste la concentration finale du gel et du chlorhydrate de lidocaïne avec une solution de tampon phosphate. On mélange manuellement le gel à la spatule pendant 10 minutes. Soit GEL1A, le gel ainsi obtenu. La concentration en acide hyaluronique de GEL1A est de 26 mg/ml. La concentration en chlorhydrate de lidocaïne de GEL1A est de 3 mg/ml. Le gel GEL1A est conditionné en seringues plastiques de 5 ml (contenant 5 ml de gel) puis stérilisé à l'autoclave à 127°C pendant 4 minutes. Soit GELlAs (= composition selon l'invention), le gel stérilisé issu de GEL1A. In 28.85 g of GEL1 gel, a powder of lidocaine hydrochloride is added and the gel is mixed manually with a spatula for 10 minutes. A solution of uncrosslinked hyaluronic acid (molecular weight approximately equal to 1.5 MDa) at 35 mg / ml is added and the gel is mixed manually with a spatula for 10 minutes. The final concentration of the gel and the lidocaine hydrochloride is adjusted with a phosphate buffer solution. The gel is mixed manually with a spatula for 10 minutes. Let GEL1A be the gel thus obtained. The hyaluronic acid concentration of GEL1A is 26 mg / ml. The concentration of lidocaine hydrochloride in GEL1A is 3 mg / ml. GEL1A gel is packaged in 5 ml plastic syringes (containing 5 ml of gel) and then sterilized in an autoclave at 127 ° C for 4 minutes. Or GELlAs (= composition according to the invention), the sterilized gel derived from GEL1A.
Dans 28.85 g de gel GEL1, on ajoute une solution de tampon phosphate afin d'ajuster la concentration finale du gel. On mélange manuellement le gel à la spatule pendant 10 minutes. Soit GEL1B, le gel ainsi obtenu. La concentration en acide hyaluronique de GEL1B est de 20 mg/ml. Le gel GEL1B est conditionné en seringues plastiques de 5 ml (contenant 5 ml de gel) puis stérilisé à l'autoclave à 125°C pendant 7 minutes. Soit GELIBs (= composition selon l'invention), le gel stérilisé issu de GEL1B. In 28.85 g of GEL1 gel, a phosphate buffer solution is added in order to adjust the final concentration of the gel. The gel is mixed manually with a spatula for 10 minutes. Let GEL1B be the gel thus obtained. The concentration of hyaluronic acid in GEL1B is 20 mg / ml. GEL1B gel is packaged in 5 ml plastic syringes (containing 5 ml of gel) and then sterilized in an autoclave at 125 ° C for 7 minutes. Either GELIBs (= composition according to the invention), the sterilized gel from GEL1B.
Dans 28.85 g de gel GEL1, on ajoute une solution de tampon phosphate afin d'ajuster la concentration finale du gel. On mélange manuellement le gel à la spatule pendant 10 minutes. Soit GEL1C, le gel ainsi obtenu. La concentration en acide hyaluronique de GEL1C est de 9 mg/ml. Le gel GEL1C est conditionné en seringues verre de 3 ml (contenant 3 ml de gel) puis stérilisé à l'autoclave à 121°C pendant 20 minutes. Soit GELICs (= composition selon l'invention), le gel stérilisé issu de GEL1C. In 28.85 g of GEL1 gel, a phosphate buffer solution is added in order to adjust the final concentration of the gel. The gel is mixed manually with a spatula for 10 minutes. Let GEL1C be the gel thus obtained. The hyaluronic acid concentration of GEL1C is 9 mg / ml. GEL1C gel is packaged in 3 ml glass syringes (containing 3 ml of gel) and then sterilized in an autoclave at 121 ° C for 20 minutes. Either GELICs (= composition according to the invention), the sterilized gel derived from GEL1C.
Exemple 2 : Caractérisation de la composition GELIBs selon l'invention La composition GELIBs selon l'invention présente les caractéristiques physico-chimiques et rhéologiques suivantes : Example 2: Characterization of the GELIBs composition according to the invention The GELIBs composition according to the invention has the following physico-chemical and rheological characteristics:
- l'élasticité G' à 0.7 Hz (et 1% de déformation) est de 244 Pa, - the elasticity G 'at 0.7 Hz (and 1% of deformation) is 244 Pa,
- le pH obtenu est de 7.42, - the pH obtained is 7.42,
- l'osmolarité obtenue est de 306 mOsmol/kg, - the osmolarity obtained is 306 mOsmol / kg,
- la concentration résiduelle en BDDE est inférieure à 1 ppm, - the residual BDDE concentration is less than 1 ppm,
- les forces d'extrusion du gel au travers des canules de 18G et 21G sont respectivement de 20 N et 28 N. - the forces of extrusion of the gel through the 18G and 21G cannulas are 20 N and 28 N respectively.
La structure monophasique de la composition GELIBs selon l'invention est observée et caractérisée par les tests suivants, comparativement à la composition injectable NASHA® (structure biphasique) à base d'acide hyaluronique réticulé de l'art antérieur : The single-phase structure of the GELIBs composition according to the invention is observed and characterized by the following tests, compared to NASHA ® injectable composition (biphasic structure) based on crosslinked hyaluronic acid of the prior art:
- une observation des structures macroscopiques des 2 compositions est réalisée à l'œil nu, après avoir déposé les gels sur une lame de verre (observation statique) : o la composition GELIBs selon l'invention présente une structure continue et homogène (une seule phase), - an observation of the macroscopic structures of the 2 compositions is carried out with the naked eye, after having deposited the gels on a glass slide (static observation): o the GELIBs composition according to the invention has a continuous and homogeneous structure (a single phase ),
o la composition NASHA® présente une structure discontinue et hétérogène (particules visibles) . o the NASHA ® composition has a discontinuous and heterogeneous structure (visible particles).
- une observation des structures microscopiques des 2 compositions est réalisée sous microscope optique (grossissement X35), après avoir déposé les gels sur une lame de verre (observation statique) : o la composition GELIBs selon l'invention présente un réseau continu et homogène (pas de particules visibles), - an observation of the microscopic structures of the 2 compositions is carried out under an optical microscope (magnification X35), after having deposited the gels on a glass slide (static observation): o the composition GELIBs according to the invention has a continuous and homogeneous network (not visible particles),
o la composition NASHA® présente un réseau discontinu et hétérogène (particules visibles). o the composition NASHA ® presents a discontinuous and heterogeneous network (visible particles).
- une observation de l'aspect et du comportement des 2 compositions est réalisée à l'œil nu en étalant les gels sur une lame de verre à l'aide d'une spatule (observation dynamique) : o la composition GELIBs selon l'invention s'étale de manière homogène et cohésive (reste en un seul morceau) en présentant un aspect souple et malléable, o la composition NASHA® s'étale de manière hétérogène et non cohésive (création de fragments et amas de gel) en présentant un aspect semi-solide (particules dures dispersées dans une phase très fluide). - the appearance and behavior of the 2 compositions are observed with the naked eye by spreading the gels on a glass slide using a spatula (dynamic observation): o the GELIBs composition according to the invention spreads out in a homogeneous and cohesive way (remains in a single piece) presenting a flexible and malleable aspect, o NASHA ® composition ranges from heterogeneous and cohesively (creation of fragments and clusters gel) having a semi-solid appearance (hard particles dispersed in a very fluid phase).
- une observation de l'aspect et du comportement des 2 compositions est réalisée à l'œil nu durant 15 minutes suite à l'ajout de 4 volumes d'une solution aqueuse physiologique (pH = 7.4) sur 1 volume de gel préalablement déposé dans une boîte de Pétri (observation statique) : o la composition GELIBs selon l'invention gonfle progressivement en absorbant le liquide. Malgré le gonflement du gel, la composition GELIBs ne change pas d'aspect, elle conserve une structure continue et homogène (une seule phase), o la composition NASHA® se disperse partiellement et se déstructure en amas/fragments au fur et à mesure qu'elle gonfle en absorbant le liquide. - observation of the appearance and behavior of the 2 compositions is carried out with the naked eye for 15 minutes following the addition of 4 volumes of a physiological aqueous solution (pH = 7.4) on 1 volume of gel previously deposited in a Petri dish (static observation): o the GELIBs composition according to the invention swells gradually while absorbing the liquid. Despite the swelling of the gel, the GELIBs composition does not change in appearance, it maintains a continuous and homogeneous structure (single phase), o NASHA ® composition is dispersed partially, and deconstructs in clusters / fragments As that '' it swells by absorbing the liquid.
- une observation de l'aspect et du comportement des 2 compositions est réalisée à l'œil nu suite à une agitation manuelle douce durant 10 secondes des gels ayant préalablement gonflé selon le test précédent (observation dynamique) : o la composition GELIBs, bien que plus volumineuse suite à son gonflement, conserve sa structure de gel et ne subit pas de changement d'aspect durant l'agitation : elle présente une structure continue et homogène (une seule phase), o la composition NASHA®, partiellement dispersée suite à son gonflement, se disperse totalement au cours de l'agitation : les particules semi-solides en suspension dans le liquide sont visibles. - observation of the appearance and behavior of the 2 compositions is carried out with the naked eye following gentle manual stirring for 10 seconds of the gels which have previously swollen according to the previous test (dynamic observation): o the composition GELIBs, although more voluminous after its swelling, retains its gel structure and does not undergo any change in appearance during agitation: it has a continuous and homogeneous structure (single phase), o NASHA ® composition partially dispersed due to its swelling, completely disperses during agitation: semi-solid particles suspended in the liquid are visible.
Les tests ci-dessus confirment que la structure de la composition selon l'invention est bien monophasique (cohésive). Elle présente une structure homogène et un aspect souple, contrairement à une composition injectable biphasique (non cohésive) à base d'acide hyaluronique réticulé de l'art antérieur, qui elle, présente une structure hétérogène (présence de particules) et un aspect semi-solide. The above tests confirm that the structure of the composition according to the invention is indeed monophasic (cohesive). It has a homogeneous structure and a flexible appearance, unlike a biphasic (non-cohesive) injectable composition based on cross-linked hyaluronic acid of the prior art, which itself has a heterogeneous structure (presence of particles) and a semi- solid.
Exemple 3 : Méthode de traitement d'un patient en utilisant la composition selon l'invention Example 3 Method of treating a patient using the composition according to the invention
Dans le cadre d'une étude clinique, une patiente âgée de 28 ans et présentant un indice de masse corporelle de 18.4 kg2/cm, a été injectée par un médecin, dans un environnement cabinet de ville (et donc non en bloc opératoire, sans anesthésie générale), dans les tissus sous-cutanés avec la composition selon l'invention (composition stérile conditionnée en seringues de volume utile de 5 ml, contenant 5 ml de gel), dans le cadre du traitement de l'augmentation du volume des fesses, pour des raisons esthétiques. As part of a clinical study, a 28-year-old patient with a body mass index of 18.4 kg 2 / cm was injected by a doctor in a city practice environment (and therefore not in the operating room, without general anesthesia), in the subcutaneous tissues with the composition according to the invention (sterile composition packaged in syringes with a useful volume of 5 ml, containing 5 ml of gel), as part of the treatment of the increase in the volume of the buttocks, for aesthetic reasons.
Après désinfection minutieuse de la zone à traiter, 145 ml de la composition selon l'invention (soit 29 seringues) ont été injectées sur la fesse droite et 135 ml (soit 27 seringues) ont été injectées sur la fesse gauche. Pour chaque fesse, l'injection a été réalisée avec une canule de 18G. Trois points d'entrée ont été utilisés par fesse afin de pouvoir administrer le produit sur l'ensemble de la surface souhaitée. Le médecin a injecté le produit sous la forme d'un bolus, combinée à une technique dite d'injection rétro-traçante. Pour chaque fesse, immédiatement après l'injection de l'ensemble des seringues, le médecin a effectué un massage de la zone traitée afin de favoriser la biodistribution et le positionnement du produit dans les tissus. After careful disinfection of the area to be treated, 145 ml of the composition according to the invention (or 29 syringes) were injected into the right buttock and 135 ml (or 27 syringes) were injected into the left buttock. For each buttock, the injection was carried out with an 18G cannula. Three entry points were used per buttock in order to be able to administer the product over the entire desired area. The doctor injected the product in the form of a bolus, combined with a technique known as retro-tracing injection. For each buttock, immediately after the injection of all the syringes, the doctor carried out a massage of the treated area in order to favor the biodistribution and the positioning of the product in the tissues.
La première visite de suivi a été effectuée après 1 mois post-injection et la deuxième visite après 6 mois afin d'évaluer le profil de sécurité et la performance de la composition selon l'invention, dans le cadre du traitement d'augmentation tissulaire réalisé. The first follow-up visit was carried out after 1 month post-injection and the second visit after 6 months in order to assess the safety profile and the performance of the composition according to the invention, in the context of the tissue augmentation treatment carried out .
L'analyse des résultats recueillis à 1 mois et 6 mois : Analysis of the results collected at 1 month and 6 months:
- confirme que la composition selon l'invention présente un très haut niveau de sécurité, c'est-à- dire une excellente tolérance dans les tissus sous-cutanés du corps, - confirms that the composition according to the invention has a very high level of safety, that is to say an excellent tolerance in the subcutaneous tissues of the body,
- confirme une bonne souplesse de la zone traitée. Le produit est bien distribué et intégré dans les tissus sous-cutanés du corps, impliquant un effet naturel de la zone traitée, visuellement et lors du toucher, - confirms good flexibility of the treated area. The product is well distributed and integrated into the subcutaneous tissues of the body, implying a natural effect of the treated area, visually and when touched,
- indique que la composition selon l'invention est efficace dans le traitement de l'augmentation du volume des fesses. L'évaluation de la performance du traitement par la patiente et un évaluateur médecin indépendant montre que les résultats obtenus à 1 mois, comme à 6 mois, présentent une amélioration significative et harmonieuse du volume des fesses, - indicates that the composition according to the invention is effective in the treatment of the increase in the volume of the buttocks. The evaluation of the performance of the treatment by the patient and an independent medical assessor shows that the results obtained at 1 month, as at 6 months, present a significant and harmonious improvement in the volume of the buttocks,
- indique un très haut niveau de satisfaction de la patiente comme du médecin injecteur. Le médecin injecteur précise notamment que la nouvelle composition selon l'invention est facile et très précise à utiliser, avec une capacité remarquable du gel à se positionner rapidement et à s'intégrer de manière appropriée dans les tissus sous-cutanés du corps tout en créant le volume souhaité. - indicates a very high level of satisfaction for both the patient and the injecting doctor. The injecting doctor specifies in particular that the new composition according to the invention is easy and very precise to use, with a remarkable capacity of the gel to position itself quickly and to integrate appropriately into the subcutaneous tissues of the body while creating the desired volume.

Claims

REVENDICATIONS
1 - Composition aqueuse injectable stérile sous forme d'hydrogel comprenant au moins de l'acide hyaluronique réticulé, ou l'un de ses sels, conditionnée dans une seringue de volume utile égal à 5 ml ± 2 ml, pour injection dans les tissus sous-cutanés du corps d'un patient humain, caractérisée en ce que : o la concentration en acide hyaluronique dans la composition est comprise entre 9 et 30 mg/ml 1 - A sterile injectable aqueous composition in the form of a hydrogel comprising at least crosslinked hyaluronic acid, or one of its salts, packaged in a syringe with a useful volume equal to 5 ml ± 2 ml, for injection into the tissues - cutaneous of the body of a human patient, characterized in that: o the concentration of hyaluronic acid in the composition is between 9 and 30 mg / ml
o l'élasticité G' à 1 Hz de la composition est comprise entre 50 Pa et 450 Pa o la structure de l'hydrogel d'acide hyaluronique réticulé est monophasique o la composition est stérilisée à la chaleur  o the elasticity G 'at 1 Hz of the composition is between 50 Pa and 450 Pa o the structure of the crosslinked hyaluronic acid hydrogel is monophasic o the composition is sterilized by heat
o le corps n'inclut pas les zones anatomiques relatives à la tête et au visage du patient humain  o the body does not include the anatomical areas relating to the head and face of the human patient
2 - Composition selon la revendication 1, caractérisée en ce que l'acide hyaluronique, ou l'un de ses sels, est le hyaluronate de sodium 2 - Composition according to claim 1, characterized in that the hyaluronic acid, or one of its salts, is sodium hyaluronate
3 - Composition selon l'une des revendications 1 à 2, caractérisée en ce que l'acide hyaluronique, ou l'un de ses sels, est réticulé en utilisant le 1,4-butanedioldiglycidyléther (BDDE) 3 - Composition according to one of claims 1 to 2, characterized in that the hyaluronic acid, or one of its salts, is crosslinked using 1,4-butanedioldiglycidylether (BDDE)
4 - Composition selon l'une des revendications 1 à 3, caractérisée en ce que la concentration résiduelle en 1,4-butanedioldiglycidyléther (BDDE) est inférieure ou égale à 1 ppm 5 - Composition selon l'une des revendications 1 à 4, caractérisée en ce que la composition est conditionnée dans une seringue possédant un volume utile égal à 5 ml 4 - Composition according to one of Claims 1 to 3, characterized in that the residual concentration of 1,4-butanedioldiglycidylether (BDDE) is less than or equal to 1 ppm 5 - Composition according to one of Claims 1 to 4, characterized in that the composition is packaged in a syringe having a useful volume equal to 5 ml
6 - Composition selon l'une des revendications 1 à 5, caractérisée en ce que la composition est conditionnée dans une seringue en matériau plastique de structure Cyclo-Olefin-Copolymer (COC) ou Cyclo-Olefin-Polymer (COP) 7 - Composition selon l'une des revendications 1 à 6, caractérisée en ce que le volume d'hydrogel dans la seringue est de 5 ml 6 - Composition according to one of claims 1 to 5, characterized in that the composition is packaged in a syringe made of plastic material of Cyclo-Olefin-Copolymer (COC) or Cyclo-Olefin-Polymer (COP) structure 7 - Composition according to one of claims 1 to 6, characterized in that the volume of hydrogel in the syringe is 5 ml
8 - Composition selon l'une des revendications 1 à 7, caractérisée en ce que l'osmolarité de la composition est comprise entre 200 et 400 mOsm/kg 9 - Composition selon l'une des revendications 1 à 8, caractérisée en ce que le pH de la composition est compris entre 6.0 et 7.9 8 - Composition according to one of claims 1 to 7, characterized in that the osmolarity of the composition is between 200 and 400 mOsm / kg 9 - Composition according to one of claims 1 to 8, characterized in that the pH of the composition is between 6.0 and 7.9
10 - Composition selon l'une des revendications 1 à 9, caractérisée en ce que l'élasticité G' à 1 Hz de la composition est comprise entre 70 Pa et 250 Pa 10 - Composition according to one of claims 1 to 9, characterized in that the elasticity G 'at 1 Hz of the composition is between 70 Pa and 250 Pa
11 - Composition selon l'une des revendications 1 à 10, caractérisée en ce que la composition contient un anesthésique local 11 - Composition according to one of claims 1 to 10, characterized in that the composition contains a local anesthetic
12 - Composition selon l'une des revendications 1 à 11, caractérisée en ce que la composition est injectée avec une canule ou une aiguille dans les tissus sous-cutanés du corps au niveau des fesses, ou des seins, ou des mollets, ou de la poitrine, ou du décolleté, ou du dos, ou des cuisses, ou des jambes, ou du ventre, ou des hanches, ou des épaules, ou des bras, ou des avant-bras, ou des mains, ou des pieds, ou des organes génitaux 12 - Composition according to one of claims 1 to 11, characterized in that the composition is injected with a cannula or a needle into the subcutaneous tissues of the body at the level of the buttocks, or the breasts, or the calves, or chest, or cleavage, or back, or thighs, or legs, or belly, or hips, or shoulders, or arms, or forearms, or hands, or feet, or genitals
13 - Méthode non thérapeutique pour augmenter, corriger, restaurer ou créer du volume au niveau du corps d'un patient, caractérisée par : 13 - Non-therapeutic method to increase, correct, restore or create volume in the body of a patient, characterized by:
> l'injection en sous-cutané, dans au moins une zone du corps du patient, d'une quantité nécessaire d'une composition aqueuse injectable stérile sous forme d'hydrogel comprenant au moins de l'acide hyaluronique réticulé, ou l'un de ses sels ; composition conditionnée dans une seringue de volume utile égal à 5 ml ± 2 ml, caractérisée en ce que : o la concentration en acide hyaluronique dans la composition est comprise entre 9 et 30 mg/ml > the injection subcutaneously, in at least one area of the patient's body, of a necessary quantity of a sterile injectable aqueous composition in the form of a hydrogel comprising at least crosslinked hyaluronic acid, or one its salts; composition packaged in a syringe with a useful volume equal to 5 ml ± 2 ml, characterized in that: o the concentration of hyaluronic acid in the composition is between 9 and 30 mg / ml
o l'élasticité G' à 1 Hz de la composition est comprise entre 50 Pa et 450 Pa o la structure de l'hydrogel d'acide hyaluronique réticulé est monophasique o la composition est stérilisée à la chaleur  o the elasticity G 'at 1 Hz of the composition is between 50 Pa and 450 Pa o the structure of the crosslinked hyaluronic acid hydrogel is monophasic o the composition is sterilized by heat
la réalisation optionnelle d'une désinfection de la zone à traiter, avant l'injection de la composition aqueuse injectable stérile  optional disinfection of the area to be treated, before injection of the sterile injectable aqueous composition
> la réalisation optionnelle d'un massage de la zone traitée, après l'injection de la composition aqueuse injectable stérile  > optional massage of the treated area, after injection of the sterile injectable aqueous composition
la zone à traiter au niveau du corps est sélectionnée dans le groupe comprenant les fesses, les seins, les mollets, la poitrine, le décolleté, le dos, les cuisses, les jambes, le ventre, les hanches, les épaules, les bras, les avant-bras, les mains, les pieds et les organes génitaux 14 - Méthode non thérapeutique selon la revendication 13, caractérisée en ce que l'acide hyaluronique, ou l'un de ses sels, contenu dans la composition aqueuse injectable stérile, est réticulé en utilisant le 1,4-butanedioldiglycidyléther (BDDE) the area to be treated at the body level is selected from the group comprising the buttocks, breasts, calves, chest, cleavage, back, thighs, legs, stomach, hips, shoulders, arms, forearms, hands, feet and genitals 14 - Non-therapeutic method according to claim 13, characterized in that hyaluronic acid, or one of its salts, contained in the sterile injectable aqueous composition, is crosslinked using 1,4-butanedioldiglycidylether (BDDE)
15 - Méthode non thérapeutique selon l'une des revendications 13 à 14, caractérisée en ce que la concentration résiduelle en 1,4-butanedioldiglycidyléther (BDDE), contenue dans la composition aqueuse injectable stérile, est inférieure ou égale à 1 ppm 15 - Non-therapeutic method according to one of claims 13 to 14, characterized in that the residual concentration of 1,4-butanedioldiglycidylether (BDDE), contained in the sterile injectable aqueous composition, is less than or equal to 1 ppm
16 - Méthode non thérapeutique selon l'une des revendications 13 à 15, caractérisée en ce que la composition aqueuse injectable stérile est conditionnée dans une seringue en matériau plastique de structure Cyclo-Olefin-Copolymer (COC) ou Cyclo-Olefin-Polymer (COP) 16 - Non-therapeutic method according to one of claims 13 to 15, characterized in that the sterile injectable aqueous composition is packaged in a syringe made of plastic material of Cyclo-Olefin-Copolymer (COC) or Cyclo-Olefin-Polymer (COP) structure )
PCT/IB2018/001235 2018-11-06 2018-11-06 Injectable composition containing hyaluronic acid, intended for the body WO2020095079A1 (en)

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