Cross-linked sodium hyaluronate and preparation method and application thereof

Abstract

The invention relates to cross-linked sodium hyaluronate and a preparation method and application thereof. The cross-linked sodium hyaluronate is prepared from raw materials, including sodium hyaluronate, an inorganic salt and a cross-linking agent. The preparation method comprises the steps: dissolving a certain amount of sodium hyaluronate in an alkaline solution with the pH value of 7.5 to 9.0, then, adding a certain amount of inorganic salt into the solution, and carrying out stirring until the inorganic salt is completely dissolved; heating the solution to the temperature of 20 DEG C to 60 DEG C, then, slowly dripping a certain volume of cross-linking agent solution into the solution, carrying out stirring, and carrying out a reaction for a period of time while carrying out heat preservation; adjusting the pH to 7.1 to 7.5 with acid, carrying out balancing for 1 to 2 hours, then, carrying out precipitation with ethanol or an ethanol solution, so as to obtain lumpy solids, i.e., the cross-linked sodium hyaluronate. By the method provided by the invention, the cross-linking efficiency of the cross-linked sodium hyaluronate can be increased, the reaction yield can be increased, side reactions can be reduced, and the residual of the cross-linking agent can be reduced; the prepared cross-linked sodium hyaluronate is safe and non-toxic, is good in stability, long in in-vivo retention time and good in filling effect and is applicable to in-vivo injection.

Description

technical field [0001] The invention belongs to the technical field of medical supplies, and in particular relates to a cross-linked sodium hyaluronate and a preparation method and application thereof. Background technique [0002] Hyaluronic acid (HA), also known as hyaluronic acid, is the most representative of mucopolysaccharides. It is widely distributed in various parts of the human body. Physiological functions, such as lubricating joints, regulating the permeability of blood vessel walls, regulating protein, water and electrolyte diffusion and operation, promoting wound healing, etc. In addition, hyaluronic acid has a special water-locking effect and is the most moisturizing substance found in nature so far. It is called an ideal natural moisturizing factor (Natural moisturizing factor, NMF), for example: 2% pure hyaluronic acid The aqueous solution can firmly hold 98% moisture. [0003] Human skin contains a large amount of hyaluronic acid, which is used to improve...

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Problems solved by technology

[0006] In the preparation schemes disclosed in the prior art, most of the sodium hyaluronate and the crosslinking agent carry out the crosslinking reaction under certain alkaline conditions, such as the preparation scheme disclosed in the patent CN 104086788 A, which is characterized in that sodium hyaluronate and The cross-linking agent performs cross-linking reaction in sodium hydroxide solution with pH>10, and the reaction under strong alkali conditions may lead to changes in the molecular configuration of hyaluronic acid, and may also cause other side reactions, resulting in more impurities in the product. It is not conducive to the biocompatibility of the product; in the preparation scheme disclosed in the patent CN101538377A, the sodium hyaluronate and the cross-linking agent are also subjected to a cross-linking reaction under concentrated alkali conditions, and after the reaction, a series of swelling, dialysis, etc. Process to remove residual cross-linking agent, complex process, high industrialization cost; patent CN 101036808 B discloses a preparation process of cross-linked sodium hyaluronate gel preparation, characterized in that divinyl sulfone and sodium hyaluronate molecules The hydroxyl group reacts to form an ether bond. The steps are: add the sodium hyaluronate raw material to the alkaline reagent, stir to dissolve it, mix the alkaline sodium hyaluronate solution with divinyl sulfone to form cross-linked hyaluronic acid Sodium clot; Patent CN 101878230 B discloses a method for cross-linking hyaluronic acid in an emulsion, the steps of which are: (a) providing an alkaline aqueous solution comprising hyaluronic acid or its salt; (b) in the organic phase or in the oil phase, from the mixed solution of step (a) to form microdroplets with desired size to form water-in-organic or water-in-oil (W / O) emulsions; (c) adding cross-linking a solution of an agent whereby hyaluronic acid reacts with said cross-linking agent to provide cross-linked hyaluronic acid microbeads; and (d) optionally processing the cross-linked hyaluronic acid microbeads obtained in step (c) dispersion of beads

This method is not only complicated to prepare, the process is cumbersome, and is not conducive to industrialization, but also needs to add organic reagents to the reaction system, which may bring risks such as organic reagent residues; patent WO97 / 04012 discloses a polysaccharide (including hyaluronic acid) gel The preparation method of the composition, the main process is: 1) forming a water-soluble cross-linkable polysaccharide aqueous solution; 2) starting cross-linking in the presence of a multifunctional cross-linking agent; 3) sterically hindering cross-linking before the gel reaction occurs The reaction prevents its termination (e.g. by diluting the solution); 4) reintroducing unsterically hindered conditions into the activated polysaccharide (e.g. by evaporating the solution) to continue the cross-linking reaction and form a viscoelastic gel

This method reacts in aqueous solution, because the solubility of sodium hyaluronate in water is relatively small, and the steric hindrance between macromolecules is relatively large, the reaction is difficult to carry out; patent 2006 / 0194758 A1 discloses mixing high and low molecular weight hyaluronic acid The reaction produces a single-phase colloid with good mechanical properties, which improves the injectability, but after the reaction of this method, a large amount of unreacted cross-linking agent remains without dialysis purification, and its concentration exceeds 300ppm. Dialysis to purify attempts to remove the cross-linker, but it is not effective, it is difficult to effectively remove the unreacted cross-linker

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