Injectable crosslinked hyaluronic acid gel and preparation method thereof

Abstract

The invention relates to an injectable crosslinked hyaluronic acid gel and a preparation method thereof. The injectable crosslinked hyaluronic acid gel is prepared by blending hyaluronic acid gel granules and chlorinated sodium phosphate physiological buffer solution; the hyaluronic acid gel granules are prepared by comprising the steps of crosslinking treatment, emulsion crosslinking granulation, purification and drying and swelling, filling and sterilization technologies. The hyaluronic acid gel granules are uniform in granule size, the residual of the crosslinking agent is less than 0.2ppm, the injection pushing is proper, and the in-vivo degradation time can last more than 8-12 months. The implant has an excellent esthetical restoration effect, is applicable to being injected to and subcutaneous dermis deep layer to subcutaneous superficial layer, restoration of moderate to severe wrinkles or folds, and can satisfy the restoration demand of wrinkles or folds caused due to skin aging.

Description

technical field [0001] The invention belongs to the technology of medical cosmetology and plastic surgery, and in particular relates to an injectable cross-linked hyaluronic acid gel and a preparation method thereof. Background technique [0002] Soft tissue fillers have been widely used in cosmetic surgery to improve facial contours, correct wrinkles, fill in sunken scars, and fill volumes (such as lips). At present, the commonly used injectable soft tissue filling materials at home and abroad are mainly hyaluronic acid products. As cosmetic injection implants, this type of product has obvious advantages, such as stable and long-lasting wrinkle repair effect after injection, and no need for excessive injection. Excess can also be treated with hyaluronidase immediately; hyaluronic acid has good biocompatibility, and the incidence of adverse reactions after operation is very low. Hyaluronic acid with proper cross-linking process can maintain the effect in the body for a long ...

AI Technical Summary

Problems solved by technology

The polyether vinyl sulfone prepared by this method has a long molecular chain and a large molecular space hindrance. It is not effective to react with hyaluronic acid molecules as a cross-linking agent, and the product effectiveness cannot meet the requirements; patent 200580047101.3 through the buffer Flush the gel to remove the cross-linking agent residue, and then add preservatives. This method cannot effectively remove the cross-linking agent inside the gel, and the addition of preservatives is not conducive to the biocompatibility of the product.

Chinese patents 200610152600.5, 200810009194.6, 200810097847.0, etc. use glycidyl ether as the cross-linking agent of hyaluronic acid, wherein 200610152600.5 dissolves hyaluronic acid in sodium hydroxide solution, adds glycidyl ether cross-linking agent to cross-link, and uses NaCl solution to remove the cross-linking agent. However, as verified by the inventors, the effect of removing glycidyl ether residues by this method is not good, and good product biocompatibility cannot be guaranteed; using aldehydes to cross-link hyaluronic acid, such as Chinese patent 200610078103.5, the The aldehyde compounds used in the patent, such as glutaraldehyde, are highly toxic, and the biocompatibility of the prepared hyaluronic acid is not high, and adverse reactions such as implant calcification are prone to occur

In addition, there are also patents that use multiple cross-linking techniques to prepare cross-linked hyaluronic acid gels, such as Chinese patents 200610152600.5, 00804642.5, etc., among which 200610152600.5 discloses a method for preparing hyaluronic acid by secondary cross-linking: first use glycidyl ether to cross-link Hyaluronic acid is treated with a coupling agent, and then dissolved in an alkaline solution, and then cross-linked with a glycidyl ether cross-linking agent. This method doubles the amount of solvent during the second cross-linking, resulting in a larger spatial structure, so The dosage of the second cross-linking agent is increased to 2.5-6 times of the first cross-linking, and the consumption and residue of the cross-linking agent are more, which is not conducive to product cost and biocompatibility

[0008] Chinese patent 200380111009.X uses carbodiimide as a cross-linking agent for hyaluronic acid. Carbodiimide cross-linking agents are unstable in aqueous solution, and verified by the inventors, this method adds carbon dioxide to the raw material of hyaluronic acid. After imine cross-linking agent, a solid gel is formed in a short time, and the cross-linking agent is difficult to mix evenly, and the cross-linking effect is not uniform, which will affect the stability of product degradation time

200810097847.0 Use hyaluronic acid and glycidyl ether to react at 15-35°C for 24 hours to obtain cross-linked hyaluronic acid gel. The cross-linking temperature is low and the cross-linking effect is not good, so the long-term effectiveness of the product cannot be guaranteed

The disadvantage of this method is that the optimal reaction of most crosslinking agents requires different chemical environments, and it is difficult to use the same buffer environment for simultaneous crosslinking reactions of multiple crosslinking agents; secondly, the order of multiple crosslinking agents Cross-linking may be due to changes in the conformation and spatial distribution of hyaluronic acid after a certain cross-linking reaction occurs, thus hindering or interfering with other cross-linking reactions; in addition, the use of multiple cross-linking agents may lead to the removal of various cross-linking The cost of the residue of the joint agent increases, and the risk of product safety increases

[0010] It can be seen from the above that the various cross-linked hyaluronic acid patent technologies and preparation methods currently disclosed have certain shortcomings, and there is still room for optimization in terms of clearly controlling the degree of cross-linking, particle size distribution range, degradation cycle, and cross-linking agent residues

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