HYDROGEL BASED ON ZINC GLUCONATE AND HYALURONIC ACID ESTERS.

Abstract

A hydrogel is disclosed containing hyaluronic acid esterified at its free hydroxyls with lipoic acid or with lipoic acid and formic acid, or a pharmaceutically acceptable salt thereof, and zinc gluconate; a process for preparing the hydrogel, compositions containing it, and the use of the hydrogel and compositions thereof in the pharmaceutical and cosmetic fields, or as a topical or injectable medical device, are also disclosed.

Description

HYDROGEL BASED ON ZINC GLUCONATE AND HYALURONIC ACID ESTERS FIELD OF INVENTION The present invention relates to a hydrogel containing zinc gluconate and hyaluronic acid esters, a process for preparing the same, compositions containing it, and the use of the hydrogel and compositions thereof in the pharmaceutical and cosmetic fields, or as injectable medical devices. BACKGROUND OF THE TECHNIQUE Zinc is a trace element that is essential for the body. It is involved in pro-inflammatory cytokine modulation mechanisms and exhibits radical scavenging activity against reactive oxygen species (ROS) [AS Prasad, Frontiers in Nutrition, 2014, Vol. 1 pp. 1-10]. It plays an important role in disorders such as osteoarthritis, which involves the massive production of free radicals, and low zinc levels have been found in patients with this disorder [A. Mierzecki, Biol Trace Elem. Res., 2011, 143, pp. 854-862]. Zinc gluconate is used for its antibacterial properties and its effect in accelerating the wound-healing process. Zinc is normally administered orally, absorbed in the intestine and rapidly sequestered in the plasma by proteins; it has a very rapid recovery and does not accumulate in the body [M. Jarosz, Inflammopharmacol, 2017, 25, pp. 11-24]. Hyaluronic acid is a glycosaminoglycan consisting of repeating units of glucuronic acid and N-acetylglucosamine linked alternately by β1^4 and β1^3 glycoside bonds. It is an essential component of connective tissue and is also present in synovial fluid, vitreous humor, and the umbilical cord. Publication WO2009 / 098127 discloses a biocompatible injectable zinc delivery product containing, dispersed in a matrix, a zinc saccharide salt such as zinc hyaluronate or zinc gluconate. The product can be used in medical devices or in medicinal or cosmetic preparations, for example, for the treatment of wrinkles, arthritis, and inflammation. The lipoate ester or lipoate / formate ester of hyaluronic acid is a derivative in which the hydroxyl groups of hyaluronic acid are esterified with lipoic acid residues or lipoic and formic acid residues, with varying degrees of substitution (DS). DS refers to the number of hydroxyl groups involved in an ester bond with lipoate or lipoate / formate residues per unit. CQaenn / zznz / E / YiAi of hyaluronic acid repeating disaccharide. Hyaluronic acid lipoate / formate ester is known to have anti-inflammatory, antioxidant and skin-protective properties (WO2009080220), and its use in the field of trichology has also been reported (WO2012080223). Lipoic acid (or thioctic acid) is a naturally occurring molecule, isolated from mammalian livers, that acts as an essential cofactor for several enzymatic reactions, including the conversion of pyruvate to acetyl-CoA in the Krebs cycle. In the body, lipoic acid regulates the production of antioxidant vitamins C and E, and glutathione. It also exhibits radical scavenging activity in lipid tissues. It has a high affinity for metals, forming stable, water-insoluble complexes [1 Fuchs Lipoic acid in health and disease]. The affinity of lipoic acid for transition metals, specifically zinc, allows for the preparation of a system that prolongs the metal's residence time in the body and the performance of its beneficial biological activities in terms of anti-inflammatory activity and free radical scavenging. However, the low water solubility of this complex makes such use very difficult. The purpose of the present invention is to provide a system particularly suitable for delivering zinc and is characterized by optimal viscoelastic properties for topical and injectable applications (mesodermal, subdermal and intra-articular) that are useful in the cosmetic and pharmaceutical fields or in medical devices. DETAILED DESCRIPTION OF THE INVENTION The object of the present invention is a hydrogel containing: - hyaluronic acid esterified at free hydroxyl groups with lipoic acid or lipoic acid and formic acid, or a pharmaceutically acceptable salt thereof; - zinc gluconate. The use of a strongly hydrophilic carrier such as hyaluronic acid or a salt thereof, modified by the introduction of lipoate residues and, optionally, formate residues, with an esterification reaction at the hydroxyl group level, constitutes the ideal system for forming a complex between the lipoic acid residue and zinc that is soluble in an aqueous solvent. The absence of a lipoic acid carboxyl group, normally involved in complex formation with the metal because it is involved in esterification at the hydroxyl group level of hyaluronic acid, is redundant due to the use of the zinc-gluconic acid salt. Because the hyaluronic acid carboxyl group is not involved, the water solubility remains unchanged. The esterified acid according to the invention preferably has a molecular weight ranging from 1 kDa to 4x103 kDa. CQaenn / zznz / E / YiAi According to a preferred modality, the number of lipoic acid residues per unit of hyaluronic acid GIcNAc-GlcUA disaccharide ranges from 0.01 to 0.5, while the amount of formic acid residues, again per unit of hyaluronic acid GIcNAc-GlcUA disaccharide, ranges from 0 to 0.1. According to another preferred modality, the amount of zinc gluconate varies between 0.1 and 25 by weight compared to sodium hyaluronate lipoate or sodium hyaluronate lipoate / formate. Preferably, esterified hyaluronic acid takes the form of a pharmacologically acceptable salt and, more preferably, the sodium salt. The characteristics and preparation of lipoic and formic ethers of hyaluronic acid are described in publication WO2009 / 080220, which is incorporated herein by reference as if inserted verbatim. With regard to the synthesis, special reference is made to page 5, line 20 to page 7, line 5, and to Examples 1 to 5 of publication WO2009 / 080220. Another aspect of the present invention relates to a process for preparing the hydrogel, which comprises mixing esterified hyaluronic acid or a salt thereof with zinc gluconate in water to obtain a viscous solution. This solution is then allowed to stand for a period ranging from 1 to 48 hours, during which the typical viscoelastic solution of a hydrogel is formed. The process may also include a hydrogel sterilization step. In a preferred embodiment, the products are mixed at a temperature ranging from 20°C to 30°C. Another aspect of the invention relates to a hydrogel obtained by means of the process described above. Other aspects of the invention relate to a pharmaceutical or cosmetic composition, a supplement or medical device containing the hydrogel described therein, optionally combined with compounds or substances possessing biological activity, such as anesthetics, specifically lidocaine. The composition or device has the appropriate shape or configuration for topical, ophthalmic, or injectable administration or application of the hydrogel, specifically intradermal, mesodermal, or intra-articular administration. For topical applications, the hydrogel is preferably formulated as an oil-in-water (O / W) or water-in-oil (W / O) emulsion, or as a gel, foam, or ointment. The uses of the hydrogel are correlated with the presence of several biologically active ingredients; the typical restorative and maintenance activities of sodium hyaluronate are combined with the antioxidant properties of lipoic acid and the various biological activities of zinc gluconate, in terms of (i) interactions with proteins, in CQaenn / zznz / E / YiAi específico tioneinas (Antioxidant-like properties of Zinc In Activated Endothelial Cells. Hennig B and McCIain GJ, Journal of the American College of Nutrition, 18(2):152-158. 1999) y enzimas, tales como, 5-a-reductasa (Effect of a topical erythromycin-zinc formulation on sebum delivery. Evaluation by combined photometric-multi-step samplings with Sebutape. Pierard GE and Pierard-Franchimont C, Clinical and Experimental Dermatology, 18(5):410-413. 1993); (¡i) actividad anti-irritante y reducción del estrés oxidativo (Antioxidant-like properties of Zinc In Activated Endothelial Cells. Hennig B and McCIain GJ, Journal of the American College of Nutrition, 18(2):152-158. 1999.) Specifically, compositions usable as topical medical devices can be used to treat skin disorders such as acne, by reducing sebum production due to the modulating activity of zinc gluconate on 5-a-reductase; rash and burns, due to the combined presence of anti-irritant agents, such as sodium hyaluronate lipoate ester and zinc gluconate. The hydrogel and the compositions related to the patent may have ophthalmic applications due to the viscoelastic and moisturizing characteristics of hyaluronic acid and the antioxidant characteristics of lipoic acid. The rheological characteristics of the hydrogel, specifically the reversibility of its viscoelastic structure after the application of a force, combined with the antioxidant, lubricating, and regenerative properties of its ingredients, can make the hydrogel, according to the invention, extremely useful in injectable medical devices, such as dermal fillers or for viscosupplementation in joints. Therefore, the hydrogel and corresponding compositions can be advantageously administered by injection into the joint capsule or the dermis, where they exert a protective effect.Furthermore, the special molecular structure of the polysaccharide, which contains lipoate residues linked by an ester bond to the polymer chain, combined with the interaction of these residues with zinc gluconate that creates the viscoelastic system, modifies the three-dimensional structure of the polymer, making it more resistant to the enzymatic attack of hyaluronidase than a crosslink consisting of simple covalent interactions typical of systems currently available on the market. Furthermore, the hydrogel and its corresponding composition can be used in the cosmetic field due to the combination of emollient and moisturizing properties of the polymeric ingredient, and the soothing and regenerative properties of the zinc and lipoic acid combination. Specifically, its cosmetic uses are intended for the treatment of skin showing signs of aging (anti-aging agent) or damage caused by external factors (anti-pollution agent). Hydrogels can also be used in medicinal applications or in CQaenn / zznz / E / YiAi mesotherapy. For the applications and uses specified herein, hydrogels can be used in combination with substances such as lidocaine, vitamins, and amino acids. The following examples illustrate the invention in greater detail. EXAMPLES Methods Instrumentation used: • VARIAN 500 MHz VNMR spectrometer equipped with a 5 mm multinuclear inverse probe with a z gradient for determining the degree of substitution (DS); • Antón Rheometer for MCR 301 equipped with parallel plates (diameter of 25 mm, with satin finish) with thermostat temperature at 25°C. Degree of substitution (DS) The degree of substitution in lipoic esters in the hyaluronic acid derivative was quantified by NMR spectroscopy. The XH NMR spectrum was performed in D2O using a 500 MHz VARIAN VNMR spectrometer, equipped with a 5 mm multinuclear inverted probe with a Z gradient. The tests were performed with the probe thermostat set to 24.85°C (298 K). The quantification of DS in lipoic ester was performed after exhaustive hydrolysis with NaOD, directly in the NMR tube. The 1H NMR spectrum of the hydrolysate allows the integration of signals attributable to lipoic acid (methylene and methine protons) and those attributable to hyaluronic acid (two anomeric protons); their proportion determines the degree of substitution. Determination of elastic and viscous moduli by rheometry tests The rheology tests of the gels were performed with an Anton Para MCR 301 Rheometer equipped with parallel plates (diameter of 25 mm, with satin finish) with a thermostat temperature of 25°C. The mechanical spectrum was recorded for each gel in oscillation mode (stress sweep) at a constant frequency of 1 Hz, which allowed the determination of the elasticity modulus G' and the viscosity modulus G (unit of measurement Pa); for some gels the flow curve was also recorded, which measures the viscosity η (unit of measurement Pa*s) in the variation of the applied force. CQaenn / zznz / E / YiAi EXAMPLE 1 Synthesis of sodium hyaluronate liDoate / formate (MW: 1500 kDa; DSi¡d: 0.4; DSfOr: 0.02) 100 ml of formamide and 5 g of HNa with a molecular weight of 1500 kDa were introduced into a 1-liter reactor. The mixture was set to a temperature of 95°C and kept under stirring at a constant temperature for 1 hour, until the polymer was completely dissolved. The temperature was then reduced to 25°C, and the mixture was kept under stirring overnight. The following day, the temperature was increased to 40°C. Sodium carbonate (264 mg Na₂CO₃) was then added, followed by the addition of a lipoylimidazolide solution in acetone (24.0 g; 20%) after 0.5 hours and then for approximately 1.5 hours. The mixture was stirred for another 0.5 hours at the same temperature. The thermostat was then turned off, and the reaction was cooled by adding 100 mL of acidic water. The product was isolated by precipitation with acetone and subsequent vacuum filtration. The crude reaction product is purified by several washes with acetone and methanol, each followed by vacuum filtration. The precipitate is then dried under vacuum at room temperature for approximately 17 hours. 10 mg of the sample were solubilized in 0.9 ml of deuterium oxide (D2O), and transferred to an NMR test tube. After hydrolysis of lipoic and formic esters by adding NaOD (deuterized sodium hydroxide), the NMR spectrum shows a DS of 0.4 in lipoic acid and 0.02 in formic acid. EXAMPLE 2 Synthesis of sodium hyaluronate liDoate / formate (MW: 300 kDa; DSi¡P: 0.5; DSfOr: 0.03) 100 mL of formamide and 10.05 g of HNa with a molecular weight of 300 kDa were introduced into a 1-liter reactor. The mixture was set to a temperature of 95°C and kept under stirring at a constant temperature for 1 hour, until the polymer was completely dissolved. The temperature was then reduced to 25°C, and the mixture was kept under stirring overnight. The following day, the temperature was increased to 40°C; then sodium carbonate (Na₂CO₃ - 528 mg) was added, and after 0.5 hours, a lipoylimidazolide solution in acetone (25.0 g; 20%) was added over approximately 1.5 hours. The mixture was stirred for 0.5 hours at the same temperature. The reaction was cooled by adding 80 mL of acidic water, and the The CQaenn / zznz / E / YiAi product was isolated by precipitation with acetone and subsequent vacuum filtration. The crude reaction product is purified by several washes with acetone and methanol, each followed by vacuum filtration. The precipitate is then dried under vacuum at room temperature for approximately 6 hours. 10 mg of the sample were solubilized in 0.9 ml of deuterium oxide (D2O), and transferred to an NMR test tube. After hydrolysis of lipoic and formic esters by adding NaOD (deuterized sodium hydroxide), the NMR spectrum shows a DS of 0.5 in lipoic acid and 0.03 in formic acid. EXAMPLE 3 Synthesis of sodium hyaluronate / lidoate (MW: 50 kDa; DSiíp: 0.5; DSfOr: 0.03) 100 mL of formamide and 10.0 g of HNa with a molecular weight of 50 kDa were introduced into a 1-liter reactor. The mixture was set to a temperature of 95°C and kept under stirring at a constant temperature for 1 hour, until the polymer was completely dissolved. The temperature was then reduced to 25°C, and the mixture was kept under stirring overnight. The following day, the temperature was increased to 40°C; then sodium carbonate (Na₂CO₃ - 500 mg) was added, and after 0.5 hours, a lipoylimidazolide solution in DMSO (20.0 g; 20%) was added for approximately 1.5 hours. The mixture was stirred for 0.5 hours at the same temperature. The reaction was cooled by adding 40 mL of acidic water, and the product was isolated by precipitation with acetone and subsequent vacuum filtration. The crude reaction product is purified by several washes with acetone and methanol, each followed by vacuum filtration. The precipitate is then dried under vacuum at room temperature for approximately 18 hours. 10 mg of the sample were solubilized in 0.9 ml of deuterium oxide (D2O), and transferred to an NMR test tube. After hydrolysis of lipoic and formic esters by adding NaOD (deuterized sodium hydroxide), the NMR spectrum shows a DS of 0.5 in lipoic acid and 0.03 in formic acid. EXAMPLE 4 Synthesis of sodium hyaluronate / lidoate (MW: 1500 kDa: DSiip: 0.3: DSfor: 0.02) CQaenn / zznz / E / YiAi 200 mL of formamide and 10.0 g of HNa with a molecular weight of 1500 kDa were introduced into a 1-liter reactor. The mixture was set to a temperature of 95°C and kept under stirring at a constant temperature for 1 hour, until the polymer was completely dissolved. The temperature was then reduced to 25°C, and the mixture was kept under stirring overnight. The following day, the temperature was increased to 40°C; then sodium carbonate (527 mg Na₂CO₃) was added, and after 0.5 hours, a lipoylimidazolide solution in acetone (47.2 g; 20%) was added for approximately 1.75 hours. The mixture was stirred for 0.5 hours at the same temperature. The reaction was cooled by adding 80 mL of acidic water, and the product was isolated by precipitation with acetone and subsequent vacuum filtration. The crude reaction product is purified by several washes with acetone and methanol, each followed by vacuum filtration. The precipitate is then dried under vacuum at room temperature for approximately 18 hours. 10 mg of the sample were solubilized in 0.9 ml of deuterium oxide (D2O), and transferred to an NMR test tube. After hydrolysis of lipoic and formic esters by adding NaOD (deuterized sodium hydroxide), the NMR spectrum shows a DS of 0.3 in lipoic acid and 0.02 in formic acid. EXAMPLE 5 Synthesis of sodium hyaluronate liDoate / formate (MW: 300 kDa; DSi¡P: 0.3; DSfOr: 0.01) 160 mL of formamide and 8 g of HNa with a molecular weight of 300 kDa were introduced into a 1-liter reactor. The mixture was set to a temperature of 95°C and kept under stirring at a constant temperature for 1.5 hours, until the polymer was completely dissolved. The temperature was then reduced to 25°C, and the mixture was kept under stirring overnight. The following day, sodium carbonate (Na₂CO₃ - 400 mg) was added, and after 0.5 hours, a lipoyl-imidazolide solution in acetone (15 g; 20%) was added for approximately 1.75 hours. The mixture was stirred for 0.5 hours at the same temperature. The reaction was cooled by adding 16 mL of acidic water, and the product was isolated by precipitation with acetone and subsequent vacuum filtration. The crude reaction product is purified by several washes with acetone and methanol, each followed by vacuum filtration. The precipitate is then dried under vacuum at room temperature for approximately 18 hours. CQaenn / zznz / E / YiAi 10 mg of the sample were solubilized in 0.9 ml of deuterium oxide (D2O), and transferred to an NMR test tube. After hydrolysis of lipoic and formic esters by adding NaOD (deuterized sodium hydroxide), the NMR spectrum shows a DS of 0.3 in lipoic acid and 0.01 in formic acid. EXAMPLE 6 Synthesis of sodium hyaluronate lyooate / formate (MW: 50 kDa; DSiíp: 0.3; DSfPr: 0.01) Thirty milliliters of formamide and three grams of HNa with a molecular weight of 50 kDa were introduced into a 500 ml three-necked flask. The mixture was heated to 95°C and stirred at a constant temperature for one hour, until the polymer was completely dissolved. The temperature was then reduced to 25°C, and the mixture was stirred overnight. The following day, the temperature was increased to 40°C; then sodium carbonate (Na₂CO₃ - 150 mg) was added, and after 0.5 hours, a lipoylimidazolide solution in DMSO (15.0 g; 20%) was added for approximately 1.5 hours. The mixture was stirred for 0.5 hours at the same temperature. The reaction was cooled by adding 10 mL of acidic water, and the product was isolated by precipitation with acetone and subsequent vacuum filtration. The crude reaction product is purified by several washes with acetone and methanol, each followed by vacuum filtration. The precipitate is then dried under vacuum at room temperature for approximately 18 hours. 10 mg of the sample were solubilized in 0.9 ml of deuterium oxide (D2O), and transferred to an NMR test tube. After hydrolysis of lipoic and formic esters by adding NaOD (deuterized sodium hydroxide), the NMR spectrum shows a DS of 0.3 in lipoic acid and 0.01 in formic acid. EXAMPLE 7 Synthesis of sodium hyaluronate lycoate / formate (80 MW, 1500 kDA: 20 MW 300 kDa; DSiío: 0.3; DSfor: 0.02^ CQaenn / zznz / E / YiAi 100 mL of formamide were introduced into a 1-liter reactor, followed by 4 g of HNa with a molecular weight of 1500 kDa and 1 g of HNa with a molecular weight of 300 kDa. The mixture was heated to 90°C and stirred at a constant temperature for 1 hour, until the polymer was completely dissolved. The temperature was then reduced to 25°C, and the mixture was stirred overnight. The following day, the temperature was increased to 40°C; then sodium carbonate (264 mg Na₂CO₃) was added, and after 0.5 hours, a lipoylimidazolide solution in acetone (31.5 g; 20%) was added over approximately 1.5 hours. The mixture was stirred for 0.5 hours at the same temperature. The reaction was cooled by adding 40 mL of acidic water, and the product was isolated by precipitation with acetone and subsequent vacuum filtration. The crude reaction product is purified by several washes with acetone and methanol, each followed by vacuum filtration. The precipitate is then dried under vacuum at room temperature for approximately 19 hours. 10 mg of the sample were solubilized in 0.9 ml of deuterium oxide (D2O), and transferred to an NMR test tube. After hydrolysis of lipoic and formic esters by adding NaOD (deuterized sodium hydroxide), the NMR spectrum shows a DS of 0.3 in lipoic acid and 0.02 in formic acid. EXAMPLE 8 Synthesis of sodium hyaluronate lycoate / formate (20 MW, 1500 kDA: 80 MW 300 kDa; PSiipi 0.3: PSfor. 0.02) 100 ml of formamide followed by 1 g of HNa with a molecular weight of 1500 kDa and 4 g of HNa with a molecular weight of 300 kDa were introduced into a 1-liter reactor. The mixture was set to a temperature of 95°C and kept under stirring at a constant temperature for 1 hour, until the polymer was completely dissolved. The temperature was then reduced to 25°C, and the mixture was kept under stirring overnight. The following day, the temperature was increased to 40°C. Sodium carbonate (264 mg Na₂CO₃) was then added, followed by the addition of a lipoylimidazolide solution in acetone (31.5 g; 20%) after 0.5 hours. The mixture was stirred for another 0.5 hours at the same temperature. The reaction was quenched by adding 40 mL of acidic water. The product was isolated by precipitation with acetone and subsequent vacuum filtration. The crude reaction product is purified by several washes with acetone and methanol, each followed by vacuum filtration. The precipitate is then dried under vacuum at room temperature for approximately 19 hours. 10 mg of the sample were solubilized in 0.9 ml of deuterium oxide (D2O), and transferred to an NMR test tube. CQaenn / zznz / E / YiAi After hydrolysis of lipoic and formic esters by adding NaOD (deuterized sodium hydroxide), the NMR spectrum shows a DS of 0.3 in lipoic acid and 0.02 in formic acid. EXAMPLE 9 Preparation of the hydrogel containing a zinc aluconate and sodium hyaluronate lipoate / formate complex (2 w / V; MW: 1500 kDa; DSi¡P: 0.4; DSfOr: 0.02; Zn 0.1 mM) 100 ml of water for injection, 4.6 g of zinc gluconate, and 0.9 g of NaCl were introduced into a 200 ml flask; and 2 g of the sample from Example 1 was added to the mixture. The system was mixed with an Ultra-Turrax. After centrifugation, the mixture was dispensed into syringes. A gel with the following characteristics was obtained: Hmax = 68000 Pa*s; G': 399.6 Pa; G: 88.7 Pa. Some syringes are subjected to an autoclave sterilization cycle (121°C; 15 min). A gel with the following characteristics is obtained: Hmax = 42000 Pa*s; G': 98.1 Pa; G: 29.7 Pa. EXAMPLE 10 Preparation of the hydrogel containing a zinc aluconate and sodium hyaluronate lipoate / formate complex (2 w / V; MW: 300 kDa; DSi¡P: 0.5; DSfOr: 0.03; Zn 0.1 mM) 100 ml of sterile water for injection, 4.5 mg of zinc gluconate, and 0.9 g of NaCl were introduced into a 200 ml flask; and 2 g of the sample from Example 2 was added to the mixture. The system was mixed with an Ultra-Turrax. After centrifugation, the mixture was dispensed into syringes. A gel with the following characteristics was obtained: G: 117.9; Pa; G: 33.1 Pa. Some syringes are subjected to an autoclave sterilization cycle (121°C; 15 min). A gel with the following characteristics is obtained: nmax = 200,000 Pa*s; G': 134.3 Pa; G: 7.7 Pa. CQaenn / zznz / E / YiAi EXAMPLE 11 Preparation of the hydrogel containing a zinc gluconate and sodium hyaluronate / formate complex (2 w / v; MW: 50 kDa; PSi: 0.5; DSfOr: 0.03; Zn 0.1 mM) 100 ml of sterile water for injection, 4.5 mg of zinc gluconate, and 0.9 g of NaCl were introduced into a 200 ml flask; and 2 g of the sample from Example 3 was added to the mixture. The system was mixed with an Ultra-Turrax. After centrifugation, the mixture was dispensed into syringes. EXAMPLE 12 Preparation of the hydrogel containing a zinc gluconate and sodium hyaluronate lipoate / formate complex (2 w / v; MW: 1500 kDa; DSiP: 0.4; DSiOr: 0.02; Zn 0.2 mM) 100 ml of sterile water for injection, 9.1 mg of zinc gluconate, and 0.9 g of NaCl were introduced into a 200 ml flask; and 2 g of the sample from Example 1 was added to the mixture. The system was mixed with an Ultra-Turrax. After centrifugation, the mixture was dispensed into syringes. Some syringes are subjected to an autoclave sterilization cycle (121°C; 15 min). A gel with the following characteristics is obtained: Hmax = 40000 Pa*s; G': 46.8 Pa; G: 12.6 Pa. EXAMPLE 13 Preparation of the hydrogel containing a zinc gluconate and sodium hyaluronate lipoate / formate complex (2 w / v; MW: 300 kDa; PSiD: 0.5; DSfOr: 0.03; Zn 0.2 mM) 100 ml of sterile water for injection, 9.1 mg of zinc gluconate, and 0.9 g of NaCl were introduced into a 200 ml flask; and 2 g of the sample from Example 2 was added to the mixture. The system was mixed with an Ultra-Turrax. After centrifugation, the mixture was dispensed into syringes. coQenn / zznz / E / YiAi EXAMPLE 14 Preparation of the hydrogel containing a zinc gluconate and sodium hyaluronate lipoate / formate complex (MW: 50 kDa; PSi¡D: 0.5; DSfor: 0.03; Zn 0.2 mM) 100 ml of sterile water for injection, 9.2 mg of zinc gluconate, and 0.9 g of NaCl were introduced into a 200 ml flask; and 2 g of the sample from Example 3 was added to the mixture. The system was mixed with an Ultra-Turrax. After centrifugation, the mixture was dispensed into syringes. EXAMPLE 15 Preparation of the hydrogel containing a zinc gluconate and sodium hyaluronate lipoate / formate complex (2 w / v; MW: 1500 kDa; DSiIP: 0.4; DSfOr: 0.02; Zn 0.15 mM) 100 ml of sterile water for injection, 6.8 mg of zinc gluconate, and 0.9 g of NaCl were introduced into a 200 ml flask; and 2 g of the sample from Example 1 was added to the mixture. The system was mixed with an Ultra-Turrax. After centrifugation, the mixture was dispensed into syringes. Some syringes are subjected to an autoclave sterilization cycle (121°C; 15 min). A gel with the following characteristics is obtained: Hmax = 16500 Pa*s; G': 17.9 Pa; G: 6.3 Pa. EXAMPLE 16 Preparation of the hydrogel containing a sodium hyaluronate lipoate / formate complex and zinc gluconate (2 w / V: 50:50; MW: 1500 kDa; PSi: 0.3; DSfOr: 0.02; MW: 300 kPa; PSi: 0.5; PSfor: 0.03; Zn 0.1 mM) 100 mL of sterile water for injection, 4.6 mg of zinc gluconate, 0.9 g of NaCl, and 0.3 g of lidocaine were introduced into a 200 mL flask. 1 mg of the sample from Example 4 and 1 mg of the sample from Example 2 were added to the mixture. The system was mixed using an Ultra-Turrax. After centrifugation, the sample is dispensed into syringes, which are then subjected to an autoclave sterilization cycle (121°C; 15 mins.). A gel with the following characteristics is obtained: nmax = 2400 Pa*s; G': 19.6 Pa; G: 5.5 Pa. coQenn / zznz / E / YiAi EXAMPLE 17 Preparation of the hydrogel containing a zinc gluconate and sodium hyaluronate / formate complex (2 w / V; 20:80; MW: 1500 kPa; PSi¡p: 0.3; PSfor: 0.02; + MW: 300 kDa; DSi¡„: 0.5; DSfnr: 0.03; Zn 0.1 mM) 100 mL of sterile water for injection, 4.6 mg of zinc gluconate, 0.9 g of NaCl, and 0.3 g of lidocaine were introduced into a 200 mL flask. 0.4 mg of the sample from Example 4 and 1.6 mg of the sample from Example 2 were added to the mixture. The system was mixed using an Ultra-Turrax. After centrifugation, the sample is dispensed into syringes, which are then subjected to an autoclave sterilization cycle (121°C; 15 mins.). A gel with the following characteristics is obtained: qmax = 57,500 Pa*s; G': 53.4 Pa; G: 5.7 Pa. EXAMPLE 18 Preparation of the hydrogel containing a zinc gluconate and sodium hyaluronate lipoate / formate complex (2 w / V; 50:50; MW: 1500 kPa; PSi₁p: 0.3; PSf₁p: 0.02; + MW: 300 kPa; PSi₁p: 0.5; PSf₁p: 0.03; Zn 0.2 mM) 100 mL of sterile water for injection, 9.2 mg of zinc gluconate, and 0.9 g of NaCl were introduced into a 200 mL flask. 1 mg of the sample from Example 4 and 1 mg of the sample from Example 2 were added to the mixture. The system was mixed using an Ultra-Turrax. After centrifugation, the sample is dispensed into syringes, which are then subjected to an autoclave sterilization cycle. EXAMPLE 19 Preparation of hydrogel containing a sodium hyaluronate lipoate / formate complex and zinc gluconate (2 w / V; PShp: 0.3; PSfOr: 0.02; Zn 0.2 mM) 100 ml of sterile water for injection, 9.1 mg of zinc gluconate, 0.9 g of NaCl, and 0.3 g of lidocaine were introduced into a 200 ml flask. 2 g of the sample from Example 8 were added to the mixture. The system was mixed using an Ultra-Turrax. After centrifugation, the sample is dispensed into syringes, which are then subjected to an autoclave sterilization cycle (121°C; 15 mins.). A gel with the following characteristics is obtained: qmax: 1800 Pa*s; G': 6.0 Pa; G: 5.2 Pa. coQenn / zznz / E / YiAi EXAMPLE 20 Preparation of the hydrogel containing a zinc gluconate and sodium hyaluronate lipoate / formate complex (80: 20 MW: 1500 kDa; DSiIP: 0.3; DSfPr: 0.02; + MW: 300 kDa; DSiIP: 0.5; DSfOr: 0.03; Zn 0.1 mM) 100 mL of sterile water for injection, 4.5 mg of zinc gluconate, 0.9 g of NaCl, and 0.3 g of lidocaine were introduced into a 200 mL flask. 1.6 mg of the sample from Example 4 and 0.4 mg of the sample from Example 2 were added to the mixture. The system was mixed using an Ultra-Turrax. After centrifugation, the mixture was dispensed into syringes. EXAMPLE 21 Preparation of hydrogel containing a lipoate / formate complex of sodium hyaluronate and zinc gluconate (2 w / V; DSiIP: 0.3; DSiPr: 0.02; Zn 0.2 mM) 100 ml of sterile water for injection, 9.2 mg of zinc gluconate, 0.9 g of NaCl, and 0.3 g of lidocaine were introduced into a 200 ml flask. 2 g of the sample from Example 7 were added to the mixture. The system was mixed using an Ultra-Turrax. After centrifugation, the mixture was dispensed into syringes. EXAMPLE 22 Preparation of hydrogel containing a lipoate / formate complex of sodium hyaluronate and zinc gluconate (4 w / V; DSi¡P: 0.3; PSfOr: 0.02; Zn 0.2mM) 100 ml of sterile water for injection, 9.2 mg of zinc gluconate, 0.9 g of NaCl, and 0.3 g of lidocaine were introduced into a 200 ml flask. 4 g of the sample from Example 7 were added to the mixture. The system was mixed using an Ultra-Turrax. After centrifugation, the sample is dispensed into syringes, which are then subjected to an autoclave sterilization cycle (121°C; 15 mins.). A gel with the following characteristics is obtained: qmax = 58800 Pa*s; G': 118.1 Pa; G: 40.0 Pa. EXAMPLE 23 Preparation of the hydrogel containing a lipoate / formate complex of sodium hyaluronate and zinc gluconate (6 w / v; DSiP: 0.3; DSfOr: 0.02; Zn 0.2 mM) CQoenn / zznz / E / YiAi 100 ml of water for injection, 9.2 mg of zinc gluconate, and 0.9 g of were introduced. NaCl and 0.3 g of lidocaine were placed in a 200 ml flask. 6 g of the sample from Example 7 were added to the mixture. The system was mixed with an Ultra-Turrax. After centrifugation, the sample is dispensed into syringes, which are then subjected to an autoclave sterilization cycle (121°C; 15 mins.). A gel with the following characteristics is obtained: qmax = 60000 Pa*s; G': 184.2 Pa; G: 81.2 Pa. EXAMPLE 24 Preparation of the hydrogel containing a complex of sodium hyaluronate / formate and zinc gluconate (4 w / V; PSi¡p: 0.3; PSfOr: 0.02; Zn 0.2 mM) 100 mL of sterile water for injection, 9.2 mg of zinc gluconate, 0.9 g of NaCl, and 0.3 g of lidocaine were introduced into a 200 mL flask. 4 g of the sample from Example 8 were added to the mixture. The system was mixed using an Ultra-Turrax. After centrifugation, the sample is dispensed into syringes, which are then subjected to an autoclave sterilization cycle (121°C; 15 mins.). A gel with the following characteristics is obtained: qmax = 57000 Pa*s; G': 122.9 Pa; G: 35.4 Pa. EXAMPLE 25 Preparation of the hydrogel containing a lipoate / formate complex of sodium hyaluronate and zinc gluconate (6 w / V; Psi: 0.3; DSfOr: 0.02; Zn 0.2 mM) 100 ml of sterile water for injection, 9.2 mg of zinc gluconate, 0.9 g of NaCl, and 0.3 g of lidocaine were introduced into a 200 ml flask. 6 g of the sample from Example 8 were added to the mixture. The system was mixed using an Ultra-Turrax. After centrifugation, the sample is dispensed into syringes, which are then subjected to an autoclave sterilization cycle (121°C; 15 mins.). A gel with the following characteristics is obtained: qmax = 170000 Pa*s; G': 283.0 Pa; G: 84.3 Pa. EXAMPLE 26 Preparation of the hydrogel containing a zinc gluconate and sodium hyaluronate lipoate / formate complex (2 w / v; 80:20 MW: 1500 kDa; DSlip: 0.3; DSfor: 0.02; + MW: 300 kDa; DSiIP: 0.5; DSfor: 0.03; Zn 0.5 mM) 100 mL of sterile water for injection, 22.5 mg of zinc gluconate, 0.9 g of NaCl, and 0.3 g of lidocaine were introduced into a 200 mL volumetric flask. 1.6 mg of the sample from Example 4, cooenn / zznz / E / YiAi, and 0.4 mg of the sample from Example 2 were added to the mixture. The system was mixed using an Ultra-Turrax. After centrifugation, the mixture was dispensed into syringes. EXAMPLE 27 Preparation of the hydrogel containing a zinc gluconate and sodium hyaluronate / formate complex (2 w / v; MW: 300 kDa; PSi: 0.5; DSfUr: 0.03; Zn: 10 mM) 100 ml of sterile water for injection, 455 mg of zinc gluconate, and 0.9 g of NaCl were introduced into a 200 ml flask. 2 g of the sample from Example 2 were added to the mixture. The system was mixed using an Ultra-Turrax. After centrifugation, the mixture was dispensed into syringes. A gel with the following characteristics was obtained: qmax: 200000 Pa*s; G': 314 Pa; G: 29 Pa. Some syringes are subjected to an autoclave sterilization cycle (121°C; 15 min). A gel with the following characteristics is obtained: qmax = 130000 Pa*s; G': 106.5 Pa; G: 9.9 Pa. EXAMPLE 28 Preparation of the hydrogel containing a zinc gluconate v lipoate / sodium hyaluronate formate complex (2 w / v; MW: 1500 kDa; PSi: 0.3; DSfOr: 0.02; Zn 0.5 mM) 100 ml of sterile water for injection, 22.5 mg of zinc gluconate, and 0.9 g of NaCl were introduced into a 200 ml flask. 2 g of the sample from Example 4 were added to the mixture. The system was mixed using an Ultra-Turrax. After centrifugation, the mixture was dispensed into syringes. EXAMPLE 29 Preparation of the hydrogel containing a zinc gluconate and sodium hyaluronate lipoate / formate complex (2 w / v; MW: 1500 kDa; PSiD: 0.4; PSfOr: 0.02; Zn 0.5 mM) 100 ml of sterile water for injection, 22.5 mg of zinc gluconate, and 0.9 g of NaCl were introduced into a 200 ml flask. 2 g of the sample from Example 1 were added to the mixture. The system was mixed using an Ultra-Turrax. coqenn / zznz / E / YiAi After centrifugation, the mixture was dispensed into syringes. EXAMPLE 30 Preparation of the hydroael that contains a zinc aluconate complex v Sodium hyaluronate iipoate / formate (2 w / V; MW: 50 kPa; PSi¡p: 0.3; DSfOr: 0.01; Zn 0.1 mMj 100 ml of sterile water for injection, 4.5 mg of zinc gluconate, and 0.9 g of NaCl were introduced into a 200 ml flask. 2 g of the sample from Example 6 were added to the mixture. The system was mixed using an Ultra-Turrax. After centrifugation, the mixture was dispensed into syringes. EXAMPLE 31 Preparation of the hydrogel containing a zinc gluconate and sodium hyaluronate lipoate / formate complex (2 w / v; MW: 1500 kDa; PSiD: 0.3; DSfOr: 0.02; Zn 0.1 mM) 100 ml of sterile water for injection, 4.5 mg of zinc gluconate, and 0.9 g of NaCl were introduced into a 200 ml flask. 2 g of the sample from Example 4 were added to the mixture. The system was mixed using an Ultra-Turrax. After centrifugation, the mixture was dispensed into syringes. EXAMPLE 32 Synthesis of sodium hyaluronate lipoate f MW: 1500 kPa; PSiíp: 0.45; PSfOr: 0.0) 200 ml of formamide and 5 g of HNa with a molecular weight of 1500 kDa were introduced into a 1-liter reactor. The mixture was heated to 75°C and stirred at a constant temperature for 1 hour, until the polymer was completely dissolved. The temperature was then reduced to 25°C, and the mixture was stirred overnight. The following day, the temperature was increased to 40°C; then sodium carbonate (660 mg Na₂CO₃) was added, and after 0.5 hours, a lipoylimidazolide solution in acetone (46.9 g; 20%) was added over approximately 1.5 hours. The mixture was stirred for 0.5 hours at the same temperature. The reaction was cooled by adding 40 mL of acidic water, and the product was isolated by precipitation with acetone and subsequent vacuum filtration. coQenn / zznz / E / YiAi The crude reaction product is purified by several washes with acetone and methanol, each followed by vacuum filtration. The precipitate is then dried under vacuum at room temperature for approximately 19 hours. 10 mg of the sample were solubilized in 0.9 ml of deuterium oxide (D2O), and transferred to an NMR test tube. After hydrolysis of lipoic and formic esters by adding NaOD (deuterized sodium hydroxide), the NMR spectrum shows a DS of 0.45 for lipoic acid and a DS of 0.0 for formic acid. EXAMPLE 33 Preparation of the hydrogel containing a complex of sodium hyaluronate / formate and zinc gluconate (2 w / V; DSiP: 0.3; DSiOr: 0.0; Zn 0.2 mM) 100 mL of sterile water for injection, 9.2 mg of zinc gluconate, 0.9 g of NaCl, and 0.3 g of lidocaine were introduced into a 200 mL flask. 2 g of the sample from Example 32 were added to the mixture. The system was mixed using an Ultra-Turrax. After centrifugation, the mixture was dispensed into syringes. EXAMPLE 34 Enzymatic degradation of a hydrogel containing a zinc gluconate v lipoate / sodium hyaluronate formate complex (2 w / v; MW: 1500 kDa; DSiId: 0.4; DSfOr: 0.02; Zn 0.1 mM) and a commercial hydrogel based on sodium hyaluronate crosslinked with BDDE The resistance to enzymatic degradation of a hydrogel prepared as described in Example 9 (syringe containing 2 ml of 2 w / v gel; MW; 1500 kDa; DSiP: 0.4; DSfor: 0.02; Zn 0.1 mM, Zn 0.1 mM, sterilized by a heat cycle of 121°C for 15 min.) was evaluated according to the degradation kinetics by measuring the reduction in the modulus of elasticity (G) over time. 0.5 ml of gel were extruded from the syringe directly onto the lower plate of the rheometer, and the modulus of elasticity G' was evaluated at a constant frequency (1 Hz) and force (1 Pa) at a temperature of 25°C. The breakdown kinetics were carried out by adding 50 of a bovine testicular hyaluronidase solution in 30 mM acetate pH regulator with a pH of 5.5 (activity 1500 U / ml) to 0.5 ml of the gel.The reduction in the elastic modulus G' over time, indicative of polymer chain shearing, was evaluated, and the disintegration kinetics were carried out under the same experimental conditions for comparison purposes, using a common hydrogel crosslinked with BDDE (1,4-butanediol diglycidyl ether) commercially available in 1 ml syringes at a concentration of 2% in a phosphate-regulated saline solution at pH 7. After 60 minutes of hyaluronidase addition, the modulus, denoted as G'eo, was used as a comparison parameter. Table 1 below shows the measured G' values, which specify the resistance to enzymatic degradation and the residual elastic modulus after 60 minutes, compared to the initial modulus. CQaenn / zznz / E / YiAi TABLE 1 Hydrogel 2 G^zero [Pa] G'eo [Pa] Residual G' Example 9 95. 17.2 41. Commercial product crosslinked with BDDE 79. 7. 9.

Claims

1. - A hydrogel containing: - hyaluronic acid esterified at its free hydroxyls with lipoic acid or with lipoic acid and formic acid, or a pharmaceutically acceptable salt thereof; and - zinc gluconate.

2. A hydrogel according to claim 1, further characterized in that the hyaluronic acid has a molecular weight ranging from 1 kDa to 4x103 kDa.

3. The hydrogel according to claims 1 to 2, further characterized in that the number of lipoic acid residues per GIcNAc-GlcUA disaccharide unit of hyaluronic acid varies from 0.01 to 0.

5.

4. The hydrogel according to claims 1 to 3, further characterized in that the number of formic acid residues per GIcNAc-GlcUA disaccharide unit of hyaluronic acid varies from 0 to 0.

1.

5. The hydrogel according to claims 1 to 4, further characterized in that the esterified hyaluronic acid salt is the sodium salt.

6. The hydrogel according to claims 1 to 5, further characterized in that the amount of zinc gluconate varies from 0.1% to 25% by weight of sodium hyaluronate lipoate or sodium hyaluronate lipoate and formate. 7 - A process for preparing the hydrogel of claims 1 to 6, comprising the following steps: (a) mixing zinc gluconate and esterified hyaluronic acid or a salt thereof in water until a viscous solution is obtained; (b) allowing the viscous solution obtained in (a) to stand for a period of between 1 and 48 hours.

8. The process in accordance with claim 7, further characterized in that it additionally comprises the sterilization of the hydrogel.

9. The process according to claim 7, further characterized in that said mixing in water is carried out at a temperature ranging from 20°C to 30°C.

10. A hydrogel that can be obtained by the process of claims 7 to 9.

11. A pharmaceutical or cosmetic composition, or a medical device, containing the hydrogel of claims 1 to 6, and 10, optionally in combination with biologically active compounds.

12. The composition or device according to claim 11, further characterized in that said compounds are selected from lidocaine, vitamins and amino acids.

13. The composition according to claims 11 to 12, further characterized in that it is in a form suitable for selected topical administration for ocular application; injectable administration, specifically intradermal, mesodermal, intra-articular or intraocular injection; and ophthalmic administration.

14. The hydrogel according to claims 1 to 6 and 10, or a composition according to claims 11 to 13, for use in the treatment of dermatological disorders, specifically acne, erythema, and burns, or in the treatment of joint inflammation.

15. The use of the hydrogel of claims 1 to 6 and 10, or of the composition of claims 11 to 13, for treating skin imperfections or as an anti-aging or anti-pollution agent.