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

Abstract

The object of the present invention is an injectable sterile aqueous formulation, ready-to-use, resorbable, 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), the hydroxyapatite being in the form of particles with an average size of less than or equal to 200 μm; the injectable sterile aqueous formulation having viscoelastic properties such that tan δ at the frequency of 1 Hz is less than or equal to 0.60.

1 - 17 . (canceled) 
     
     
         18 . An injectable sterile aqueous formulation in the form of a particulate cohesive viscoelastic gel comprising:
 i) crosslinked hyaluronic add, or a salt thereof, at a concentration of between 1% and 4% (mass/volume), and   ii) hydroxyapatite at a concentration of between 5% and 60% (mass/volume), the hydroxyapatite being in the form of particles with an average size of less than or equal to 200 μm,   
       wherein the injectable sterile aqueous formulation exhibits viscoelastic properties wherein the tan δ at the frequency of 1 Hz is less than or equal to 0.60. 
     
     
         19 . The injectable sterile aqueous formulation of  claim 18 , wherein the molecular mass of the hyaluronic acid, or of one of its salts, is between 2.5×10 5  Dalton (Da) and 4×10 Da. 
     
     
         20 . The injectable sterile aqueous formulation of  claim 18 , wherein the formulation has been sterilized in humid heat. 
     
     
         21 . The injectable sterile aqueous formulation of  claim 18 , wherein the concentration of the crosslinked hyaluronic add or of one of its salts, is between 1% and 3% (mass/volume). 
     
     
         22 . The injectable sterile aqueous formulation of  claim 18 , wherein the concentration of the crosslinked hyaluronic add or of one of its salts, is between 1.5% and 2.5% (mass/volume). 
     
     
         23 . The injectable sterile aqueous formulation of  claim 18 , wherein the concentration of hydroxyapatite is between 10 and 50% (mass/volume). 
     
     
         24 . The injectable sterile aqueous formulation of  claim 18 , wherein the concentration of hydroxyapatite is between 20% and 40% (mass/volume). 
     
     
         25 . The injectable sterile aqueous formulation of  claim 18 , wherein the average size of the hydroxyapatite particles is less than or equal to 50 μm and greater than or equal to 10 μm. 
     
     
         26 . The injectable sterile aqueous formulation of  claim 18 , wherein the average size of the hydroxyapatite particles is greater than or equal to 10 μm. 
     
     
         27 . The injectable sterile aqueous formulation of  claim 18 , wherein the formulation further comprises one or more ceramic materials. 
     
     
         28 . The injectable sterile aqueous formulation of  claim 18 , wherein the formulation further comprises one or more anesthetics. 
     
     
         29 . The injectable sterile aqueous formulation of  claim 28 , wherein the one or more anesthetics are selected from the group consisting of lidocaine, adrenaline, procaine, etidocaine, articaine, mepivacaine, pramocaine, quinisocaine, and salts thereof. 
     
     
         30 . The injectable sterile aqueous formulation of  claim 29 , wherein the anaesthetic is lidocaine hydrochloride. 
     
     
         31 . The injectable sterile aqueous formulation of  claim 18 , wherein the formulation further comprises one or more antioxidants. 
     
     
         32 . The injectable sterile aqueous formulation of  claim 31 , wherein the one or more antioxidants are polyols. 
     
     
         33 . The injectable sterile aqueous formulation of  claim 32 , wherein the polyols are selected from the group consisting of sorbitol, glycerol, mannitol and propylene glycol. 
     
     
         34 . The injectable sterile aqueous formulation of  claim 18 , which is in the form of an esthetic filler for filling and/or restoring volumes and/or replacing biological tissues. 
     
     
         35 . A kit containing the injectable sterile aqueous formulation of  claim 18 . 
     
     
         36 . The kit of  claim 35 , wherein the injectable sterile aqueous formulation is comprised in a syringe, an ampoule or a flask. 
     
     
         37 . A method for making an injectable sterile aqueous formulation comprising the steps:
 a) preparing a first mixture comprising at least 1% to 4% by weight of crosslinked hyaluronic add, or a salt thereof, by forming covalent bonds between the chains of the hyaluronic add using bi- or poly-functional molecules to provide a crosslinked hyaluronic add with a cohesive structure,   b) purifying the first mixture,   c) adding hydroxyapatite to the purified first mixture from step b) at a concentration of between 5% and 60% (mass/volume) and dispersing the hydroxyapatite homogeneously in the purified first mixture comprising crosslinked hyaluronic acid to form a gel product,   d) converting the gel product obtained in step c) into a ready-to-use form, and   e) sterilizing the gel product in a ready-to-use form in humid heat.