US20150257989A1 - Injectable sterile aqueous formulation based on crosslinked hyaluronic acid and hydroxyapatite for aesthetic use - Google Patents

Injectable sterile aqueous formulation based on crosslinked hyaluronic acid and hydroxyapatite for aesthetic use Download PDF

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US20150257989A1
US20150257989A1 US14/433,927 US201314433927A US2015257989A1 US 20150257989 A1 US20150257989 A1 US 20150257989A1 US 201314433927 A US201314433927 A US 201314433927A US 2015257989 A1 US2015257989 A1 US 2015257989A1
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sterile aqueous
aqueous formulation
injectable sterile
hydroxyapatite
gel
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Samuel GAVARD MOLLIARD
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Anteis SA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/04—Dispersions; Emulsions
    • A61K8/042—Gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/0241—Containing particulates characterized by their shape and/or structure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A61K8/24—Phosphorous; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A61K8/735—Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/54—Polymers characterized by specific structures/properties
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/91—Injection

Definitions

  • the object of the present invention is a ready-to-use resorbable injectable sterile aqueous formulation used for aesthetic purposes as a particulate cohesive viscoelastic gel comprising i) crosslinked hyaluronic acid, or one of its salts, at a concentration of between 1% and 4% (mass/volume); the crosslinking carried out providing the possibility of obtaining a gel based on crosslinked hyaluronic acid with a so-called cohesive structure and ii) hydroxyapatite, at a concentration of between 5% and 60% (mass volume), said hydroxyapatite being in the form of particles with an average size of less than or equal to 200 ⁇ m; said injectable sterile aqueous formulation having viscoelastic properties such that tan ⁇ at the frequency of 1 Hz is less than or equal to 0.60.
  • Ageing is a natural phenomenon with which any individual is confronted. It is inevitably accompanied by a reduction in the cell activity of the human body.
  • these substances may be resorbable or non-resorbable in vivo.
  • the role of these substances is to fill the collapsed portions by creating volume in or under the skin, for treating different portions of the body, in particular the face. By this mechanical effect, the skin is re-tensioned and the wrinkles are smoothed, leading to a younger appearance of the treated area.
  • HA crosslinked hyaluronic acid
  • HA also called ⁇ stabilized HA>>
  • HA crosslinked hyaluronic acid
  • It is injected into or under the dermis in order to fill wrinkles or restore the volume of various areas of the body for a period of several months. It has the advantage of having very little secondary effects in post-injection and extremely rare complications in the long term.
  • the practitioner has the possibility of correcting his/her treatment by injecting a solution of hyaluronidases (specific enzymes of HA), a solution which will degrade the product based on crosslinked HA which was injected beforehand.
  • Injections of crosslinked HA because of their gradual disappearance (resorption of the polymer in the tissues over time) have to be repeated at regular intervals, generally from 6 to 12 months, in order to maintain the efficiency of the treatment.
  • Non-crosslinked hyaluronic acid itself has a short residence time in the skin (a half-life of less than a week), it is degraded in vivo by various factors such as radical, enzymatic, thermal and mechanical degradation. It is indeed the crosslinking which allows it to significantly increase its half-life by slowing down the degradation kinetics of hyaluronic acid according to the factors described above, thus allowing efficiency of the aesthetic treatment which may attain about 12 months.
  • resorbable filling substances exist on the dermo-aesthetics market. Mention may for example be made of products containing calcium hydroxyapatite. These particles are suspended in an aqueous phase which may contain a polymer like carboxymethylcellulose, a derivative of cellulose. The products of this family are injected into or under the dermis in order to fill the wrinkles or restore the volume of various areas of the body and in particular the face. They show a high level of biocompatibility, which justifies the absence of an allergy test before injection. For these products, very few secondary effects or complications are reported and a duration of efficiency of the order of 12 months or more is observed. From the point of view of resorption, the aqueous phase is rapidly removed from the treated area and the hydroxyapatite particles are degraded and metabolized by macrophages over time.
  • a stimulation of the endogenous production of collagen by hydroxyapatite particles is also described for these products injected into tissues of the skin.
  • the invention relates to an injectable and bioresorbable sterile aqueous formulation, used for aesthetic purposes, as a particulate cohesive viscoelastic gel comprising i) crosslinked hyaluronic acid or one of its salts, at a concentration of between 1% and 4% (mass/volume); the molecular mass of hyaluronic acid or one of its salts, being between 2.5 ⁇ 10 5 Da and 4 ⁇ 10 6 Da, the crosslinking carried out providing the possibility of obtaining a gel based on crosslinked hyaluronic acid with a so-called cohesive structure, and ii) hydroxyapatite, at a concentration of between 5% and 60% (mass/volume), said hydroxyapatite being in the form of particles with an average size of less than or equal to 200 ⁇ m; said injectable sterile aqueous formulation having viscoelastic properties such that tan ⁇ at the frequency of 1 Hz is less than or equal to 0.60.
  • the present invention relates to a method for preparing an injectable sterile aqueous formulation comprising the steps consisting of: a) preparing a first mixture comprising at least 1% to 4% by weight of crosslinked hyaluronic acid or of one of its salts, by forming covalent bonds between the chains of said biopolymer by means of bi- or poly-functional molecules, the crosslinking carried out providing the possibility of obtaining a gel based on crosslinked hyaluronic acid with a so-called cohesive structure, b) purifying said first mixture, c) then adding hydroxyapatite at a concentration comprised between 5% to 60% (mass/volume) by dispersing it homogeneously in the gel based on crosslinked hyaluronic acid, d) putting the thereby obtained gel in a ready-to-use form, e) sterilizing the product in humid heat.
  • the present invention relates to a kit preferably in the form of a syringe containing the formulation as described earlier.
  • FIG. 1 represents photographs of the comparison of the B′, X gels, and of the formulation based on CMC and hydroxyapatite, according to the tests described in Example 2.
  • the invention described hereafter has the goal of proposing a novel bioresorbable injectable sterile aqueous formulation used for cosmetic and aesthetic purposes and having specific properties of viscoelasticity, of filling and of long-term performance.
  • This formulation is characterized in that it is in the form of a particular cohesive viscoelastic gel comprising
  • crosslinked hyaluronic acid or one of its salts, at a concentration of between 1% and 4% (mass/volume), the crosslinking carried out providing the possibility of obtaining a gel based on crosslinked hyaluronic acid with a so-called cohesive structure, and ii) hydroxyapatite, at a concentration of between 5% and 60% (mass/volume), said hydroxyapatite being in the form of particles with an average size of less than or equal to 200 ⁇ m; said injectable sterile aqueous formulation having viscoelastic properties such that tan ⁇ at the frequency of 1 Hz is less than or equal to 0.60.
  • this formulation has the remarkable ability to generate volume in tissues over the long term, by means of synergy between crosslinked hyaluronic acid and hydroxyapatite particles, according to the conditions of the invention.
  • the hydroxyapatite particles (with a solid behavior: strong elasticity and negligible viscosity) considerably reinforce the elasticity of the gel and therefore its ability to generate volume by inducing significant force/pressure on the tissues in order to correct the defective area to be treated.
  • Crosslinked hyaluronic acid itself provides viscoelasticity properties, i.e. elasticity but also viscosity with which it is possible to have gel consistency coming close to that of tissues and therefore thus compensating for the very strong elasticity and the absence of viscosity provided by the hydroxyapatite particles.
  • This provides the possibility of having a product which is integrated into the tissues in a much more homogeneous way (the patient less feeling the product upon touching), less traumatic for tissues (strong limitation of inflammation in post-injection) and less painful upon injection.
  • crosslinked hyaluronic acid under the conditions of the invention, will allow considerable reduction in the migration of hydroxyapatite particles, particles which are retained within the gel, because of the strong cohesivity present on the account of the crosslinked hyaluronic acid of a cohesive type (crosslinked hyaluronic acid having low resorption kinetics).
  • This strong limitation of the migration provides the possibility of having a gel with an improved volume-forming ability over the long term and able to reduce side-effects like the occurrence of so-called hard areas, felt by the patient.
  • Hyaluronic acid is a polysaccharide consisting of the repetition of glucuronate disaccharide and N-acetyl glucosamine units. It is widely distributed among connective, epithelial and nerve tissues in humans as well as in animals. It is one of the main components of the extracellular matrix. It significantly contributes to proliferation and to migration of the cells. It is notably found in a substantial concentration in the aqueous humor, synovial liquid, skin and the umbilical cord.
  • hyaluronic acid salts with a cation for example a mono- or di-valent salt such as a sodium, potassium, magnesium, calcium, manganese salt.
  • Sodium salts are most particularly preferred.
  • hyaluronic acid or one of its salts is in a crosslinked form.
  • This crosslinking is obtained by forming covalent bonds between the chains of said biopolymer by means of bi- or poly-functional molecules, the crosslinking carried out providing the possibility of obtaining a gel based on crosslinked hyaluronic acid with a so-called cohesive, further called monophasic structure.
  • the cohesive nature of the gel based on crosslinked hyaluronic acid is a major and required specific feature of the invention.
  • the gel should not rapidly disperse when it is introduced into also water, as would a gel with a non-cohesive nature called a “biphasic” gel (type of gel based on crosslinked hyaluronic acid which is not able to maintain the hydroxyapatite particles and therefore avoid migration).
  • a “biphasic” gel type of gel based on crosslinked hyaluronic acid which is not able to maintain the hydroxyapatite particles and therefore avoid migration.
  • Example 2 brings out this difference between a cohesive and a non-cohesive gel.
  • the present invention generally comprises a concentration of crosslinked hyaluronic acid, or of one of its salts, between 1% and 4% (mass/volume) preferably between 1% and 3% (mass/volume).
  • the concentration of crosslinked hyaluronic acid, or of one of its salts is between 1.5% and 2.5% (mass/volume).
  • the concentration of crosslinked hyaluronic acid, or of one of its salts may be between 1.5% and 3% (mass/volume) or 1% and 2.5% (mass/volume).
  • the aqueous formulation according to the invention comprises hyaluronic acid, or one of its salts, the molecular mass of which is preferably between 2.5 ⁇ 10 5 Da and 4 ⁇ 10 6 Da. According to a particularly preferred alternative, this molecular mass is between 1 ⁇ 10 6 Da and 3 ⁇ 10 6 Da. Alternatively, the molecular mass is between 1 ⁇ 10 6 Da and 2.5 ⁇ 10 6 Da, or 2.5 ⁇ 10 5 Da and 3 ⁇ 10 6 Da.
  • Hydroxyapatite is a mineral species from the family of phosphates, of formula (Ca 5 (PO 4 ) 3 (OH), usually written as Ca 10 (PO 4 ) 6 (OH) 2 in order to underline the fact that the lattice of the crystal structure comprises two molecules. Hydroxyapatite belongs to the crystallographic family of apatites, isomorphous compounds having the same hexagonal structure. This compound has been used as a biomaterial for many years in various medical speciality products.
  • the present invention generally comprises a concentration of hydroxyapatite particles comprised between 5 to 60% (mass/volume), preferably between 10 to 50% (mass/volume), preferably between 20 to 40% (mass/volume) and the average size of the hydroxyapatite particles is less than or equal to 200 ⁇ m, preferably less than 50 ⁇ m, preferably greater than 10 ⁇ m.
  • the viscosity and the elasticity properties of the formulation according to the invention are optimum when the parameter tan delta or tan ⁇ , corresponding to the [viscosity modulus G′′/elastic modulus G′] ratio at the frequency of 1 Hz, is less than or equal to 0.60, preferably less than or equal to 0.58.
  • the elastic nature of the formulation according to the invention, relative to its viscosity should be sufficiently large so as to be able to avoid sedimentation of the hydroxyapatite particles.
  • the hydroxyapatite particles tend to settle over time.
  • This sedimentation involves the obtaining of a non-homogeneous formulation based on hydroxyapatite particles, which is not satisfactory for the act of injecting the formulation through a needle (blocking the needle) on the one hand and for the safety and performance of the formulation at the injection area (for example, generation of so-called hard areas in the tissues of the skin) on the other hand.
  • the cohesivity of the formulation according to the invention is a major element but it is also required that the viscoelastic nature of the latter be suitable so as to:
  • Another goal of the invention is to have a better lifetime as compared with formulations of the prior art.
  • This better lifetime of the aesthetic effect is obtained through the ability of the crosslinked hyaluronic acid to maintain over the long term the hydroxyapatite particles in the injection area and the ability of the hydroxyapatite particles to impart remarkable mechanical/rheological properties over the long term. Therefore there will be less need to renew the injections with the formulation according to the invention, the gain in lifetime in a clinical situation probably being of several months.
  • radio-opaque hydroxyapatite particles provides an advantage to the gel since they may be easily localized by the practitioner by radiography during and/or after injection.
  • the ability of the hydroxyapatite particles to stimulate the endogenous production of collagen is an important element of the invention. Slow resorption of the product in the tissues will be accompanied by production of collagen (generation of volume and elasticity), which will provide the possibility of participating in the performance of the treatment in the long term.
  • the present invention therefore consists in a formulation, as described above, used for filling and/or restoring volumes and/or replacing biological tissues, in particular i) restoring volumes of the face (cheeks, chin, cheekbones, temples, . . . ), ii) restoring volumes of the body (buttocks, breasts, hands, . . . ), iii) restoring volumes of the face in HIV patients affected by facial lipodystrophy.
  • the formulation according to the invention is generally used as such but it is not excluded that at least one other additive (other than those mentioned above) and/or at least one active ingredient are added thereto.
  • the formulation according to the invention is a ready-to-use formulation, since the practitioner does not have to mix himself/herself the crosslinked hyaluronic acid and a hydroxyapatite solution, just before the injection.
  • the formulation may further comprise one or several ceramic materials.
  • These materials are generally selected from the group comprising tri-calcium phosphate, calcium carbonate and calcium sulfate, or a combination of several of its ceramic materials.
  • the formulation according to the invention may also further comprise one or several anesthetics, selected from the group comprising lidocaine alone or in combination with adrenaline, procaine, etidocaine alone or in combination with adrenaline, articaine alone or in combination with adrenaline, mepivacaine, pramocaine, quinisocaine, or one or several of the salts of these anesthetics.
  • the selected anesthetic is lidocaine hydrochloride.
  • the formulation according to the invention may also further comprise one or several antioxidants, such as the antioxidants of the family of polyols.
  • the antioxidant may be selected from the group of polyols comprising sorbitol, glycerol, mannitol or propylene glycol.
  • the present invention relates to a method for preparing an injectable sterile aqueous formulation comprising the steps: a) preparing a first mixture comprising at least 1% to 4% by weight of crosslinked hyaluronic acid or one of its salts, by forming covalent bonds between the chains of said biopolymer by means of bi- or poly-functional molecules, the crosslinking carried out providing the possibility of obtaining a gel based on crosslinked hyaluronic acid with a so-called cohesive structure, b) purifying said first mixture, c) then adding hydroxyapatite at a concentration of between 5% and 60% (mass/volume) by dispersing it homogeneously in the gel based on crosslinked hyaluronic acid, d) converting the gel thereby obtained into a ready-to-use form, e) sterilizing the product in humid heat.
  • Sterilization of the formulation according to step e) is achieved in humid heat.
  • a heat sterilization cycle temperature and duration of the sterilization cycle
  • the following sterilization cycles in humid heat may be used: 131° C., 1 min/130° C., 3 min/125° C., 7 mins/121° C., 20 mins.
  • the present invention relates to a kit preferably in the form of a syringe containing the formulation as described earlier.
  • the present invention also relates to a kit in the form of a container other than a syringe such as an ampoule or a flask containing the formulation as described above.
  • the inventor has shown that in the following examples that the formulation according to the invention based on crosslinked HA should have specific properties, notably cohesivity properties. If such is not the case (see the examples with non-crosslinked HA or with crosslinked HA not having the claimed structure), the hydroxyapatite particles are not properly maintained within the matrix and may therefore diffuse relatively easily out of the gel, which implies a loss of volume at the treated area (i.e. a loss of efficiency) and possible complications because of this migration causing safety problems.
  • Step 1 3.5 g of sodium hyaluronate of molecular weight 2.6 MDa are added to 1% sodium hydroxide (30.5 g). The mixture is left to homogenize for 1 h 30 mins. 420 mg of butanediol diglycidyl ether (BDDE) are added to the mixture which is homogenized, closed and then placed in a water bath at 50° C. for 2 h. The mixture is then neutralized by adding 7.5 g of 1N HCl.
  • BDDE butanediol diglycidyl ether
  • the gel may finally be degassed, filled into 2 ml glass syringes and sterilized by a steam autoclave at 130° C. for 3 minutes ( ⁇ gel A/viscoelastic gel of a so-called cohesive or monophasic structure).
  • Step 2 Preparation of the gel according to the invention.
  • the gel is particulate, cohesive, viscoelastic. Indeed, the latter appears as a viscoelastic gel (it has elasticity G′ and viscosity G′′ properties/see below), having strong cohesivity (see Example 2) and containing hydroxyapatite particles.
  • the hyaluronic acid concentration of the gel is 17.5 mg/ml (1.75%) (assay with carbazole, method of the European Pharmacopeia).
  • the pH (7.15) and the osmolarity (315 mOsm/kg) of the gel are physiological values.
  • the gel is easily injectable through a needle: A force of 26.3 N is required for pushing the gel through a 21G 11 ⁇ 2 needle, considering a pushing rate of 12.5 mm/minute.
  • the gels A and B are characterized from a mechanical/rheological point of view:
  • the rheometer used for carrying out these characterizations is a AR2000 (TA Instruments) with a flat geometry of 40 mm, an air gap of 1,000 micrometers and an analysis temperature of 25° C.
  • a comparison of the parameters is carried out at 1 Hz.
  • the product B has a significantly higher elasticity than the product A.
  • the tan delta values of each of the products A and B are relatively close: the gel B retains a substantially viscous nature, in spite of the presence of the hydroxyapatite particles (which themselves have high elasticity and negligible viscosity).
  • This stronger elasticity in combination with the strong cohesivity of the product according to the invention, provides an enhanced ability of the product to generate volume in tissues.
  • a measurement of the normal force induced by the gel to be tested is carried out by compressing the sample between the Peltier plane and the geometry for an air gap of 1,500 micrometres and an amount of gel of 1.4 g.
  • the product B has a significantly stronger elasticity and induced normal force than the product A.
  • This stronger elasticity combined with the strong cohesivity of the gel according to the invention, provides an enhanced ability of the product to generate volume in tissues.
  • Calcium hydroxyapatite is then added into the gel in order to obtain a concentration of 200 mg/ml (20%) and then mixing with a spatula is carried out (2 minutes for 5 g of gel).
  • the commercial Resylane® Perlane® gel (batch 11363-1) based on crosslinked hyaluronic acid with a non-cohesive or biphasic structure, the hyaluronic acid concentration of which is 20 mg/ml (2%), is doped with 200 mg/ml (20%) of calcium hydroxyapatite by mixing with a spatula (2 minutes for 5 g of gel).
  • the gel A1 and the Restylane® Perlane® gel are compared according to the following test:
  • the Restylane® Perlane® gel has completely disaggregated/dispersed, forming a multitude of particles in the aqueous solution.
  • the Restylane® Perlane® gel does indeed have a so-called non-cohesive or biphasic structure (the gel is rapidly dispersed in the aqueous solution).
  • the gel A1 is always in the form of a ⁇ gel ball>> in the aqueous solution. It therefore indeed has a so-called cohesive or monophasic structure (the gel does not rapidly disperse in the aqueous solution, it has strong cohesivity, unlike the Restylane®Perlane® gel).
  • the gel B′ according to the invention and the gel X are compared according to the following test (see FIG. 1 ):
  • the gel X has completely disaggregated/dispersed, forming a multitude of particles in the aqueous solution.
  • the gel X has a particulate non-cohesive viscoelastic structure. It does not correspond to the characteristics of the gel according to the invention. In medical practice for a use in aesthetics, the latter will diffuse/migrate around the injection area.
  • the gel B′ itself, is always in the form of a gel ball in the aqueous solution. It therefore indeed has a particulate cohesive structure which within the scope of medical practice for use in aesthetics will give the possibility of not diffusing/migrating around the injected area, and thus avoiding complications related to the migration of hydroxyapatite particles in the tissues but also having better long term performance of the product since the injected gel will be able to maintain its ability to generate volume in tissues over a long period, in view of the absence of migration of the biomaterial of the treated area.
  • C be a gel prepared according to the same procedure (Steps 1 & 2 ) as the one described in Example 1 by introducing 200 mg of BDDE instead of 420 mg.
  • D be a gel prepared according to the same procedure (Steps 1 & 2 ) as the one described in Example 1 by introducing 290 mg of BDDE instead of 420 mg.
  • the gel C is characterized from a mechanical/rheological point of view.
  • the rheometer used for carrying out the rheological characterizations is an AR2000 (TA Instruments) with a flat geometry of 40 mm, an air gap of 1,000 micrometres and an analysis temperature of 25° C.
  • a comparison of the parameters is carried out at 1 Hz.
  • This sedimentation involves obtaining products based on non-homogeneous hydroxyapatite particles, which is not satisfactory for the act of injecting the gel through a needle (blocking of the needle) but also for the safety and the performance of the product in the injection area (significant risks of complications such as for example the generation of so-called hard areas in the tissues of the skin).
  • the cohesivity of the gel according to the invention is significant but it is also required that the viscoelastic nature of the latter be suitable so as to:
  • the elastic nature of the gel (relative to its viscosity) should therefore be sufficiently large so as to be able to avoid sedimentation of the particles.
  • a non-crosslinked HA solution with hydroxyapatite is of no interest since the non-crosslinked hyaluronic acid will be very rapidly resorbed and it will not allow migration of the hydroxyapatite particles to be prevented over the long term.
  • aqueous solution of hydroxyapatite (S1) is prepared (30% of phosphocalcium hydroxyapatite having a grain size comprised between 30 and 50 micrometers in an iso-osmolar physiological solution and having neutral pH).
  • the solution S1 is unable to maintain the hydroxyapatite particles at the injection area over the long term.
  • CMC carboxymethylcellulose
  • S3 hydroxyapatite
  • the formulation S3 is unable to maintain the hydroxyapatite particles in the injection area over the long term.

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US20170065741A1 (en) * 2012-10-08 2017-03-09 Anteis S.A. Injectable sterile aqueous formulation based on crosslinked hyaluronic acid and hydroxyapatite for aesthetic use
WO2018020501A1 (en) 2016-07-27 2018-02-01 Marbelle Threads Ltd. Threads of cross-linked hyaluronic acid and hydroxyapatite
WO2018047182A1 (en) * 2016-09-07 2018-03-15 Luminera Derm Ltd. Injectable gels comprising cross-linked hyaluronic acid and hydroxyapatite, and methods of manufacturing thereof
RU2773475C2 (ru) * 2016-09-07 2022-06-06 Аллерган Фармасьютикалз Интернешнл Лимитед Инъекционные гели, содержащие поперечно сшитую гиалуроновую кислоту и гидроксиапатит, и способы их получения
ES2947097A1 (es) * 2022-02-01 2023-08-01 Martinez Miguel Angel Gomariz Metodo cosmetico de rejuvenecimiento de la piel

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EP3381438B1 (en) 2015-11-24 2023-06-07 BMI Korea Co. Ltd Composition for injection of hyaluronic acid, containing hyaluronic acid derivative and dna fraction, and use thereof
FR3044557B1 (fr) * 2015-12-07 2017-12-01 Benedicte Vincente Gavard Molliard Tauzin Nouvelle composition injectable; procede de preparation de ladite composition; utilisation de ladite composition
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IT201700008651A1 (it) * 2017-01-26 2018-07-26 Beauty System Pharma Ltd Acido ialuronico reticolato con agenti reticolanti di tipo naturale o semisintetico
CN107496990A (zh) * 2017-08-15 2017-12-22 广东泰宝医疗器械技术研究院有限公司 一种可注射的抗菌软骨修复水凝胶及其制备方法
CA3052929A1 (en) * 2017-10-10 2019-04-18 E.N.A. Impeccable Skincare Solutions Ltd Method of manufacturing and dermal filler compositions containing hyaluronic acid and hydroxyapatite
WO2019182745A1 (en) 2018-03-19 2019-09-26 Bryn Pharma, LLC Epinephrine spray formulations
WO2019197608A1 (en) 2018-04-13 2019-10-17 Merz Pharma Gmbh & Co. Kgaa Dermal filler based on crosslinked hyaluronic acid, calcium phosphate material particles and carboxymethyl cellulose, a process for preparing same and uses thereof
CN108744054A (zh) * 2018-06-15 2018-11-06 北京水元生生物科技有限公司 一种注射型美容整形用面部填充剂组合物凝胶及其制备方法
WO2020095079A1 (fr) * 2018-11-06 2020-05-14 Kylane Laboratoires Sa Composition injectable contenant de l'acide hyaluronique pour des applications au niveau du corps
CN111166686A (zh) * 2018-11-12 2020-05-19 无锡市伙伴日化科技有限公司 一种玻尿酸爽肤水
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KR102686600B1 (ko) * 2021-08-05 2024-07-19 주식회사 바이오비쥬 가교 히알루론산을 포함하는 화장료 조성물 및 이의 제조방법
CN115137877A (zh) * 2022-03-25 2022-10-04 杭州诺嫣生物科技有限公司 注射型凝胶组合物及其制备方法和应用
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Cited By (9)

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Publication number Priority date Publication date Assignee Title
US20150238525A1 (en) * 2012-10-08 2015-08-27 Aptissen S.A. Injectable sterile aqueous formulation based on crosslinked hyaluronic acid and on hydroxyapatite, for therapeutic use
US20170065741A1 (en) * 2012-10-08 2017-03-09 Anteis S.A. Injectable sterile aqueous formulation based on crosslinked hyaluronic acid and hydroxyapatite for aesthetic use
US10463762B2 (en) * 2012-10-08 2019-11-05 Anteis S.A. Injectable sterile aqueous formulation based on crosslinked hyaluronic acid and hydroxyapatite for aesthetic use
WO2018020501A1 (en) 2016-07-27 2018-02-01 Marbelle Threads Ltd. Threads of cross-linked hyaluronic acid and hydroxyapatite
WO2018047182A1 (en) * 2016-09-07 2018-03-15 Luminera Derm Ltd. Injectable gels comprising cross-linked hyaluronic acid and hydroxyapatite, and methods of manufacturing thereof
RU2773475C2 (ru) * 2016-09-07 2022-06-06 Аллерган Фармасьютикалз Интернешнл Лимитед Инъекционные гели, содержащие поперечно сшитую гиалуроновую кислоту и гидроксиапатит, и способы их получения
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ES2947097A1 (es) * 2022-02-01 2023-08-01 Martinez Miguel Angel Gomariz Metodo cosmetico de rejuvenecimiento de la piel

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