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Preparation method of cross-linked sodium hyaluronate gel having hyaluronidase activity inhibiting effect

A technology of cross-linking hyaluronic acid and hyaluronidase, which is applied in the fields of medical science and prostheses, which can solve the problems of limited application, large pushing force, difficult small-caliber syringe needles, etc., and improve biological safety Effect

Active Publication Date: 2015-07-08
SHANGHAI QISHENG BIOLOGICAL PREPARATION CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Cross-linked sodium hyaluronate is a polymer gel obtained by chemical cross-linking modification of sodium hyaluronate, which makes up for the disadvantages of short retention time of sodium hyaluronate, while traditional cross-linked sodium hyaluronate gels are mostly granular Or the viscosity is too large, the pushing force is large, it is difficult to pass through the needle of a small-caliber syringe, etc., which limits its further application
[0004] Sodium hyaluronate gel products that appear on the market today mostly use divinyl sulfone (DVS), 1,4-butanediol bisglycidyl ether (BDDE) as cross-linking agents, in order to pursue longer in vivo degradation time, often increase the amount of cross-linking agent added to improve the cross-linking degree of the product, but most of the above-mentioned cross-linking agents are toxic or carcinogenic, and the residual cross-linking agent enters the body, which will cause great risks. At the same time, in the existing preparation During the dialysis process, since the cross-linked sodium hyaluronate gel has a three-dimensional network structure, the cross-linking agent is embedded in it and it is difficult to remove it; therefore, in order to improve the biological safety of the product, it is necessary to reduce the cross-linking The amount of agent added, but this will also affect the degree of cross-linking of the product, and ultimately affect the residual time of the product in vivo
[0005] Aiming at the above-mentioned seemingly contradictory problem, there is no relevant patent to explain the above-mentioned problem. The present invention aims at this pair of contradictions and solves the problem from another angle.

Method used

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  • Preparation method of cross-linked sodium hyaluronate gel having hyaluronidase activity inhibiting effect

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Weigh 10 g of sodium hyaluronate dry powder with a molecular weight of 1.2 million Daltons, 5 g of γ-polyglutamic acid dry powder with a molecular weight of 1 million, and use 0.5% ( w / w) hydrochloric acid solution to dissolve it, and then react at room temperature 25°C for 24 hours to obtain an acidic cross-linked gel. Then add 100 ml of 1% sodium hydroxide solution to the acidic cross-linked gel, dissolve evenly, put it in a constant temperature and humidity reaction cabinet at 5°C and react for 7 days to obtain an alkaline cross-linked gel. The secondary cross-linked gel was diluted to 1000ml with 0.5% sodium hydroxide, then precipitated with 95% ethanol, and washed twice. Then, the obtained dry powder was dissolved into 400ml by using phosphate buffer solution, and after dissolving evenly, it was put into a dialysis bag and dialyzed for 3 days to obtain sample 1.

Embodiment 2

[0026] Weigh 12 g of sodium hyaluronate dry powder with a molecular weight of 1.2 million Daltons, 5 g of γ-polyglutamic acid dry powder with a molecular weight of 1 million, and use 0.5% ( w / w) hydrochloric acid solution to dissolve it, and then react at room temperature 25°C for 48 hours to obtain an acidic cross-linked gel. Then add 100ml of potassium hydroxide solution with a concentration of 1% to the acidic cross-linked gel, dissolve evenly, put it into a constant temperature and humidity reaction cabinet at 5°C and react for 7 days to obtain an alkaline cross-linked gel. The secondary cross-linked gel was diluted to 1000ml with 0.5% potassium hydroxide, then precipitated with 95% ethanol, and washed twice. Then, the obtained dry powder was dissolved to 400ml with phosphate buffer solution, and after dissolving evenly, it was put into a dialysis bag and dialyzed for 5 days to obtain sample 2.

Embodiment 3

[0028] Weigh 12 g of sodium hyaluronate dry powder with a molecular weight of 1.2 million Daltons, 5 g of γ-polyglutamic acid dry powder with a molecular weight of 1 million, and use 0.5% ( w / w) hydrochloric acid solution to dissolve it, and then react at room temperature 25°C for 48 hours to obtain an acidic cross-linked gel. Then add 100 ml of potassium hydroxide solution with a concentration of 1% to the acidic cross-linked gel, dissolve evenly, put it in a constant temperature and humidity reaction cabinet at 5°C and react for 5 days to obtain an alkaline cross-linked gel. The secondary cross-linked gel was diluted to 1000ml with 0.5% potassium hydroxide, then precipitated with 95% ethanol, and washed twice. Then, the obtained dry powder was dissolved to 400ml with phosphate buffer solution, and after dissolving evenly, it was put into a dialysis bag and dialyzed for 5 days to obtain sample 3.

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Abstract

The invention relates to a preparation method of a cross-linked sodium hyaluronate gel having a hyaluronidase activity inhibiting effect. The method utilizes a fact that different groups in sodium hyaluronate molecules are activated under different pH conditions, then different pH conditions are controlled, a hyaluronidase inhibitor is introduced into the sodium hyaluronate molecules, and finally the cross-linked sodium hyaluronate gel having the hyaluronidase activity inhibiting effect is obtained. Compared with a gel prepared by a traditional process, the cross-linked sodium hyaluronate gel prepared by the method has the advantages of low viscosity, long in-vivo residual time and the like, also can inhibit the hyaluronidase activity, and has the highest inhibition rate up to 65%. The low viscosity of the cross-linked sodium hyaluronate gel prepared by the method ensures convenience of clinical use, and the cross-linked sodium hyaluronate gel inhibits the hyaluronidase activity, significantly increases the in-vivo residual time, and has good application prospects in the aspects of cosmetic injections, artificial vitreous bodies and degenerative arthritis supplementary treatment.

Description

technical field [0001] The invention relates to a preparation method of a cross-linked sodium hyaluronate gel inhibiting the activity of hyaluronidase. In the invention, the hyaluronidase inhibitor is firstly bound to the sodium hyaluronate gel molecule through a covalent bond, and then The gel is formed by secondary cross-linking, and the gel can be used for soft tissue filling, artificial vitreous body, joint lubricating fluid supplement, drug slow-release carrier, etc., and belongs to the medical field. [0002] technical background [0003] Hyaluronic acid is a linear polysaccharide composed of glucuronic acid and N-acetyl-glucosamine disaccharide repeating units, widely distributed in connective tissue, vitreous body, placenta and other organs and tissues of mammals. Hyaluronic acid has good biocompatibility and non-immunogenicity, and is widely used in medical, beauty, cosmetics and other fields. However, due to the specific hyaluronidase in the human body, the natur...

Claims

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Application Information

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IPC IPC(8): C08J3/24C08J3/075C08L89/00C08L77/04C08K5/1515A61L27/20
Inventor 魏长征朱彬李莉莉奚宏伟
Owner SHANGHAI QISHENG BIOLOGICAL PREPARATION CO LTD
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