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Preparation method of cross-linked hyaluronic acid filling agent for injection

A technology of cross-linked hyaluronic acid and hyaluronic acid is applied in the preparation of injectable cross-linked hyaluronic acid long-acting filler for soft tissue filling and the preparation of cross-linked hyaluronic acid filler for injection, which can solve difficult problems. Realize the problems of microsphere preparation, low mechanical properties of microspheres, and difficult operation.

Active Publication Date: 2020-10-30
BLOOMAGE BIOTECHNOLOGY CORP LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] CN10318902A discloses a preparation method of composite cross-linked sodium hyaluronate gel microspheres for facial injection. The method crushes, washes and filters secondary cross-linked sodium hyaluronate gel to obtain cross-linked sodium hyaluronate gel Microspheres, the operation is difficult, and it is difficult to realize the preparation of microspheres
CN 103848995 A discloses a method for preparing hyaluronic acid nanospheres. The method needs to prepare two kinds of functionalized hyaluronic acid, namely thymine functionalized hyaluronic acid and adenine functionalized hyaluronic acid, and then Cross-linking to prepare microspheres is cumbersome, and the preparation process involves a variety of organic solvents, making industrial production difficult
CN 103333351 A and CN 104387600 A respectively disclose a process for preparing cross-linked sodium hyaluronate microspheres which can be used as an embolism by using sodium hyaluronate as a raw material and a composite cross-linked sodium hyaluronate gel for facial injection. The preparation method of glue microspheres, these two methods are similar, all are to add hyaluronic acid gel into emulsified liquid emulsification first, then add cross-linking agent to emulsified liquid to carry out cross-linking, this method needs a large amount of cross-linking agent, And the cross-linking agent is difficult to penetrate into the gel, resulting in low cross-linking efficiency, uneven cross-linking, low mechanical properties of the microspheres, and easy to break

Method used

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  • Preparation method of cross-linked hyaluronic acid filling agent for injection
  • Preparation method of cross-linked hyaluronic acid filling agent for injection
  • Preparation method of cross-linked hyaluronic acid filling agent for injection

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] This example mainly studies the effect of the sodium hyaluronate content in the aqueous phase on the cross-linked sodium hyaluronate microspheres. The preparation method is as follows:

[0043] 1. Maintain a low temperature environment of 2-8°C, add 0.4g BDDE to 16mL water and mix well, then add different qualities of sodium hyaluronate (molecular weight 2000KDa), mix well to get gel 1, add 20 mL 1 to gel 1 Wt% NaOH solution was dispersed by a high-shear dispersing emulsification homogenizer at a speed of 15,000 rpm for 20 min to obtain gel 2, which is the aqueous phase.

[0044] 2. Add gel 2 to 400mL n-octane containing 2wt% Span80, emulsify with a high-shear dispersing emulsifying homogenizer at 20,000 rpm for 10 minutes, and let stand to remove air bubbles after emulsification is uniform.

[0045] 3. After the emulsification is completed, the temperature of the emulsion is controlled at 30°C, and it is stirred for 12 hours to carry out cross-linking.

[0046] 4. Aft...

Embodiment 2

[0051] This example mainly studies the effect of the amount of cross-linking agent in the water phase on the cross-linked sodium hyaluronate microspheres. The preparation method is as follows:

[0052] 1. Maintain a low temperature environment of 2-8°C, add BDDE of different qualities to 16mL water and mix well, then add 4 g sodium hyaluronate (molecular weight 2000KDa), mix well to obtain gel 1, add 20 mL 1 to gel 1 Wt% NaOH solution was dispersed by a high-shear dispersing emulsification homogenizer at a speed of 15,000 rpm for 20 min to obtain gel 2, which is the aqueous phase.

[0053] 2. Add gel 2 to 400mL cyclohexane containing 2wt% Span80, and emulsify with a high-shear dispersing emulsifying homogenizer at 20,000 rpm for 10 minutes. After the emulsification is uniform, let stand to remove air bubbles.

[0054] 3, with embodiment 1.

[0055] 4, with embodiment 1.

[0056] 5. Same as embodiment 1.

[0057] The amount of crosslinking agent is shown in Table 2 below.

...

Embodiment 3

[0060] This example mainly studies the influence of crosslinking temperature and crosslinking time on crosslinked sodium hyaluronate microspheres. The preparation method is as follows:

[0061] 1. Maintain a low temperature environment of 2-8°C, add 0.4g BDDE to 16mL water and mix well, then add 4 g sodium hyaluronate (molecular weight 2000KDa), mix well to obtain gel 1, add 20 mL 1 wt% to gel 1 NaOH solution was dispersed by a high-shear dispersing emulsification homogenizer at a speed of 15,000 rpm for 20 min to obtain gel 2, which is the aqueous phase.

[0062] 2, with embodiment 1.

[0063] 3. After the emulsification is completed, the temperature and time of the emulsion are controlled to carry out cross-linking.

[0064] 4, with embodiment 1.

[0065] 5. Same as embodiment 1.

[0066] The crosslinking temperature and crosslinking time are shown in Table 3 below.

[0067]

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Abstract

The invention discloses a preparation method of a cross-linked hyaluronic acid filling agent for injection. The method comprises the following steps: preparing cross-linked hyaluronic acid microspheres by a low-temperature control reversed-phase emulsification cross-linking technique, uniformly mixing the cross-linked hyaluronic acid microspheres with hyaluronic acid gel, and drying to obtain thefilling agent. The microsphere has the characteristics of simple preparation steps, mild reaction conditions, less cross-linking agent dosage, good cross-linking uniformity, high safety and the like;the obtained filler contains non-crosslinked hyaluronic acid and crosslinked hyaluronic acid microspheres at the same time, can achieve the purposes of quickly filling pits and maintaining a long filling effect at the same time, can be quickly degraded by taking measures during excessive correction or misoperation, reduces the risk of product injection, and is suitable for being applied to the field of soft tissue filling.

Description

technical field [0001] The invention relates to a preparation method of a cross-linked hyaluronic acid filler for injection, in particular to a preparation method of an injectable cross-linked hyaluronic acid long-acting filler for medical cosmetic filling, especially for soft tissue filling, which belongs to tissue filling and the field of medical biomaterials technology. Background technique [0002] Hyaluronic acid is an acidic mucopolysaccharide composed of D-glucuronic acid and N-acetylglucosamine. It has good biocompatibility and has been used in the fields of medicine and cosmetics. It is a research hotspot nowadays. Due to the poor stability of natural sodium hyaluronate gel, sensitivity to hyaluronidase and free radicals, short retention time in vivo, and poor mechanical strength, the mechanical properties and properties of sodium hyaluronate gel can be enhanced by chemical modification and cross-linking. Anti-enzymatic properties, so it can last longer in the body...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61L27/20A61L27/52A61L27/50A61L27/58C08J3/24C08J3/12C08L5/08
CPCA61L27/20A61L27/52A61L27/50A61L27/58C08J3/24C08J3/12C08J2305/08A61L2430/34A61L2400/06C08L5/08
Inventor 苏江伟吴万福潘存才张燕刘建建郭学平
Owner BLOOMAGE BIOTECHNOLOGY CORP LTD
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