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Preparation method of cross-linked hyaluronic acid microspheres

A technology of cross-linked hyaluronic acid and hyaluronic acid, which is applied in medical science, bulk delivery, prosthesis, etc., can solve the problems of difficult preparation of microspheres, low mechanical properties of microspheres, and difficult operation

Active Publication Date: 2020-10-30
BLOOMAGE BIOTECHNOLOGY CORP LTD
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  • Abstract
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  • Claims
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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 microspheres
  • Preparation method of cross-linked hyaluronic acid microspheres
  • Preparation method of cross-linked hyaluronic acid microspheres

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] 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:

[0036] 1. Maintain a low temperature environment of 2-8°C, add 0.1g BDDE to 16mL water and mix well, then add sodium hyaluronate (molecular weight 2000KDa) of different quality, 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 5000 rpm for 10 min to obtain Gel 2, which is the aqueous phase.

[0037] 2. Add gel 2 to 400mL n-octane containing 2wt% Span80, emulsify with a high-shear dispersing emulsifying homogenizer at 10,000 rpm for 10 minutes, and let stand to remove air bubbles after emulsification is uniform.

[0038] 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.

[0039] 4. After the...

Embodiment 2

[0044] 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:

[0045] 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 5000 rpm for 10 min to obtain Gel 2, which is the aqueous phase.

[0046] 2. Add gel 2 to 400mL cyclohexane containing 2wt% Span80, emulsify with a high-shear dispersing emulsifying homogenizer at 10,000 rpm for 10 minutes, and let stand to remove air bubbles after emulsification is uniform.

[0047] 3, with embodiment 1.

[0048] 4, with embodiment 1.

[0049] 5. Same as embodiment 1.

[0050] The amount of crosslinking agent is shown in Table 2 below.

[0051]...

Embodiment 3

[0053] This example mainly studies the influence of crosslinking temperature and crosslinking time on crosslinked sodium hyaluronate microspheres. The preparation method is as follows:

[0054] 1. Maintain a low temperature environment of 2-8°C, add 0.1g 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 For NaOH solution, a high-shear dispersing emulsification homogenizer was used to break up the gel at a speed of 5000 rpm for 10 min to obtain gel 2, which is the aqueous phase.

[0055] 2, with embodiment 1.

[0056] 3. After the emulsification is completed, the temperature and time of the emulsion are controlled to carry out cross-linking.

[0057] 4, with embodiment 1.

[0058] 5. Same as embodiment 1.

[0059] The crosslinking temperature and crosslinking time are shown in Table 3 below.

[0060]

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Abstract

The invention discloses a preparation method of cross-linked hyaluronic acid microspheres. The method comprises the following steps: uniformly mixing and dispersing hyaluronic acid or salt thereof, across-linking agent, alkali and water at low temperature to obtain a water phase; adding the water phase into an oil phase containing an emulsifier, and fully emulsifying to obtain an emulsion; and cross-linking the emulsion at a cross-linking temperature, removing the oil phase after cross-linking, and carrying out post-treatment to obtain the cross-linked hyaluronic acid microspheres. The cross-linked hyaluronic acid microspheres which are uniform in particle and high in mechanical property are prepared by using a small amount of cross-linking agent through a low-temperature control reversed-phase emulsification cross-linking technology, are controllable in particle size, have certain expansibility and can be applied to the fields of drug-loaded microspheres and cosmetic filling.

Description

technical field [0001] The invention relates to a preparation method of cross-linked hyaluronic acid microspheres, belonging to the technical field of biomedical polymer materials. 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 shortcomings of natural sodium hyaluronate hydrogel, such as poor stability, sensitivity to hyaluronidase and free radicals, short retention time in vivo, and poor mechanical strength, it is usually chemically modified and cross-linked to obtain a A series of new bioactive and functional sodium hyaluronate gels, the mechanical strength, stability and degradation resistance of these gels have been enhanced, and can last longer in the body, expanding the hyaluronic acid in Applications in the fields of biomedicine and tissue engineering...

Claims

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Application Information

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IPC IPC(8): C08J3/24C08J3/12C08J3/03C08L5/08A61K9/16A61L27/20A61L27/50
CPCC08J3/24C08J3/12C08J3/03A61K9/1652A61L27/20A61L27/50C08J2305/08
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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