Silanized hyaluronic acid as well as synthesis method and application thereof

Abstract

The invention discloses silanized hyaluronic acid as well as a synthesis method and application thereof, and belongs to the technical field of biological material synthesis. The synthesis method of the silanized hyaluronic acid comprises the following steps: dissolving hyaluronic acid in a bio-based solvent to form a hyaluronic acid solution; mixing the hyaluronic acid solution with an amino-containing silane coupling agent, and carrying out a first reaction to form an intermediate reactant; mixing the intermediate reactant with a catalyst, and carrying out a second reaction to form silanized hyaluronic acid; the bio-based solvent is glycerol and / or hexafluorophosphate ionic liquid; the catalyst is an ionic liquid loaded metal oxide. The invention provides the environment-friendly and efficient synthesis method of the silanized hyaluronic acid, and the synthesized silanized hyaluronic acid has higher silicon content, is a water-soluble macromolecule and can meet the application requirements of the silanized hyaluronic acid in cosmetics, health care products and medical auxiliary materials.

Description

Technical Field

[0001] The present application relates to the technical field of biomaterial synthesis, and in particular to a silanized hyaluronic acid and a synthesis method and application thereof. Background Art

[0002] Hyaluronic acid (HA), also known as hyaluronic acid, is a natural high molecular mucopolysaccharide composed of repeated connections of N-acetylglucosamine and D-glucuronic acid disaccharide units. It is a natural high molecular non-sulfated glycosaminoglycan with excellent water solubility and biodegradability. It is widely distributed in the extracellular matrix of soft connective tissue of human body and animals, and has many important physiological functions, such as maintaining extracellular space, regulating osmotic pressure, lubrication, etc. In terms of wound healing, HA can regulate cell adhesion, migration, differentiation and proliferation, reduce inflammatory response, and also has the characteristics of improving cell infiltration, scavenging free radicals and anti-oxidation. Therefore, it has very important application value in the fields of medical beauty, health care, biomedicine, etc.

[0003] Although HA has excellent properties such as high biocompatibility, biodegradability, high hydrophilicity and viscoelasticity, its high hydrophilicity leads to poor lipophilicity, which leads to problems such as short half-life, rapid degradation in the body and short in situ residence time, resulting in low bioavailability. However, the HA structure contains chemically active sites such as hydroxyl and carboxyl groups, and can be chemically modified in various ways to obtain specific functions. Reported hyaluronic acid derivatives include acetylated hyaluronic acid, quaternized hyaluronic acid, carboxymethylated hyaluronic acid, silanized hyaluronic acid, etc. Among them, silanized hyaluronic acid has better moisturizing properties, no cytotoxicity, no skin irritation, and can promote the proliferation of keratinocytes. It can be used to prepare cosmetics and pharmaceutical excipients with skin moisturizing and repair functions.

[0004] There is a method that discloses mixing a hyaluronic acid solution and a sodium silanol solution and then adjusting the pH with a resin to obtain a hyaluronic acid composite aqueous solution. However, the final product of this method is a liquid with a relatively low concentration, which results in a large volume and difficulties in packaging, storage and transportation. There is a method that discloses a preparation method for silanized hyaluronic acid, but the reaction raw material chlorosilane in this method is very sensitive to water, decomposes rapidly when in contact with water, and forms smoke during the dripping process, decomposing to generate hydrochloric acid, which is highly corrosive. Therefore, there are strict requirements during its storage and use, and the preparation method needs to be strictly controlled to operate under anhydrous conditions, and the conditions are very harsh.

[0005] In addition, the silanized hyaluronic acid synthesized by traditional methods has the following problems: 1) When the silanized hyaluronic acid is a water-soluble macromolecule, the degree of silanization is low (i.e., the silicon content of the silanized hyaluronic acid is low), which cannot effectively improve the performance of the hyaluronic acid; 2) When the degree of silanization is high, the cross-linking degree of the prepared silanized hyaluronic acid is too high and it cannot be dissolved in water. It can only be used in hydrogel products, which limits its application.

[0006] Based on the above situation, the development of a green preparation process for water-soluble silanized hyaluronic acid has very important practical value and economic benefits. Summary of the invention

[0007] Based on this, the main purpose of the present application is to provide an environmentally friendly and efficient method for synthesizing silanized hyaluronic acid. The synthesized silanized hyaluronic acid has a high silicon content and is a water-soluble macromolecule with broad application prospects.

[0008] In a first aspect of the present application, a method for synthesizing silanized hyaluronic acid is provided, comprising the following steps:

[0009] dissolving hyaluronic acid in a bio-based solvent to form a hyaluronic acid solution;

[0010] The hyaluronic acid solution is mixed with an amino-containing silane coupling agent to perform a first reaction to form an intermediate reactant;

[0011] The intermediate reactant is mixed with a catalyst to perform a second reaction to form silanized hyaluronic acid;

[0012] The bio-based solvent is glycerol and / or hexafluorophosphate ionic liquid; and the catalyst is a metal oxide supported by the ionic liquid.

[0013] In some embodiments, the amino-containing silane coupling agent includes N-(2-aminoethyl)-3-aminopropyltrimethoxysilane and / or 3-aminopropyltrimethoxysilane.

[0014] In some embodiments, the hexafluorophosphate ionic liquid includes at least one of 1-butyl-3-methylimidazolium hexafluorophosphate, 1-propyl-3-methylimidazolium hexafluorophosphate, 1-ethyl-3-methylimidazolium hexafluorophosphate, 1,3-dimethylimidazolium hexafluorophosphate, and 1-hexyl-3-methylimidazolium hexafluorophosphate.

[0015] In some embodiments, in the catalyst, the ionic liquid is a hexafluorophosphate ionic liquid, and the metal oxide includes ZrO 2 .

[0016] In some embodiments, the mass volume ratio of the hyaluronic acid to the bio-based solvent is 1 g: (30-60) mL;

[0017] and / or the mass ratio of the hyaluronic acid to the amino-containing silane coupling agent is 1:(0.2-0.6);

[0018] And / or the mass ratio of the hyaluronic acid to the catalyst is 1:(0.05-0.2).

[0019] In some embodiments, the conditions of the first reaction include: reacting at room temperature for 1.5-4h;

[0020] The conditions of the second reaction include: microwave power of 200-500W, reaction temperature of 50-75°C, and reaction time of 2-4h.

[0021] In some embodiments, the step of performing a second reaction further includes the steps of purification and drying.

[0022] In some embodiments, the purification comprises dialysis and / or resin adsorption.

[0023] In some embodiments, the drying comprises at least one of natural drying, oven drying and freeze drying.

[0024] In some embodiments, the dialysis uses an ultrafiltration membrane of 10000-15000Da.

[0025] In some embodiments, the freeze-drying conditions include: freeze-drying temperature of -60 to -40°C; freeze-drying time of 20 to 40 hours.

[0026] The second aspect of the present application provides silanized hyaluronic acid synthesized by the aforementioned synthesis method.

[0027] In some embodiments, the silicon content of the silanized hyaluronic acid is ≥ 4%.

[0028] The third aspect of the present application provides the use of the aforementioned silanized hyaluronic acid in cosmetics, health products and pharmaceutical excipients.

[0029] Beneficial effects of this application:

[0030] 1. The present application provides an environmentally friendly and efficient method for synthesizing silanized hyaluronic acid, which uses an amino-containing silane coupling agent as a modifier to achieve simultaneous amidation and silanization, thereby improving the degree and efficiency of modification and simplifying the synthesis steps; and uses bio-based solvents and environmentally friendly catalysts to reduce the negative impact on the environment and improve the biocompatibility and safety of the product.

[0031] 2. The silanized hyaluronic acid synthesized in the present application has a high silicon content and is a water-soluble macromolecule, which can meet the application requirements in cosmetics, health products and pharmaceutical excipients. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the following briefly introduces the drawings required for use in the embodiments or the prior art description. The drawings are only used to illustrate the preferred implementation methods and are not considered to be limitations of the present application. The same reference symbols are used throughout the drawings to represent the same components. In the drawings:

[0033] Figure 1 is the infrared spectrum of the silanized hyaluronic acid prepared in Example 1;

[0034] Figure 2 This is a diagram showing the appearance of the aqueous solution of silanized hyaluronic acid in Example 1. DETAILED DESCRIPTION

[0035] In order to make the purpose, technical solution and advantages of this application clearer and to provide a more thorough and comprehensive understanding of the disclosed content of this application, the technical solution of this application will be clearly and completely described below in conjunction with the specific embodiments of this application and the corresponding drawings. The described embodiments are only part of the embodiments of this application, not all of them.

[0036] The implementation of the present application is described in detail below in conjunction with the accompanying drawings. This embodiment is implemented based on the technical solution of the present application, and a detailed implementation method and specific operation process are given, but the protection scope of the present application is not limited to the following embodiments.

[0037] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this application belongs. The terms used herein in the specification of this application are only for the purpose of describing specific embodiments and are not intended to limit this application.

[0038] the term

[0039] Unless otherwise specified or incompatible herewith, the terms and phrases used herein shall have the following meanings:

[0040] In the present application, "plurality", "multiple" and the like, unless otherwise specified, refer to a number greater than or equal to 2. For example, "one or more" or "at least one" means one or greater than or equal to two.

[0041] In the present application, the terms "further", "particularly" and the like are used for descriptive purposes to indicate differences in content, but should not be construed as limiting the scope of protection of the present application.

[0042] In the present application, the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.

[0043] In the present application, when it comes to a numerical interval (i.e., a numerical range), unless otherwise specified, the distribution of the optional numerical values ​​in the numerical interval is considered to be continuous, and includes the two numerical endpoints (i.e., the minimum value and the maximum value) of the numerical interval, and each numerical value between the two numerical endpoints. Unless otherwise specified, when the numerical interval only refers to the integers in the numerical interval, it includes the two endpoint integers of the numerical range, and each integer between the two endpoints, which is equivalent to directly listing each integer. When multiple numerical ranges are provided to describe features or characteristics, these numerical ranges can be combined. In other words, unless otherwise specified, the numerical range disclosed herein should be understood to include any and all sub-ranges included therein. The "numerical value" in the numerical interval can be any quantitative value, such as a number, a percentage, a ratio, etc. "Numerical interval" allows broadly including numerical interval types such as percentage intervals, ratio intervals, and ratio intervals.

[0044] In the present application, the term "room temperature" generally refers to 4-35° C., preferably 20±5° C. In the embodiments of the present application, room temperature refers to 20-30° C.

[0045] In this application, unless otherwise specified, the temperature parameter is allowed to be either a constant temperature treatment or to vary within a certain temperature range. It should be understood that the constant temperature treatment allows the temperature to fluctuate within the accuracy range controlled by the instrument. Fluctuations within the range of ±5°C, ±4°C, ±3°C, ±2°C and ±1°C are allowed.

[0046] In this application, when referring to the unit of a data range, if there is a unit only after the right endpoint, it means that the units of the left and right endpoints are the same. For example, 2-5h means that the units of the left endpoint "2" and the right endpoint "5" are both time (h).

[0047] In a first aspect of the present application, a method for synthesizing silanized hyaluronic acid is provided, comprising the following steps:

[0048] dissolving hyaluronic acid in a bio-based solvent to form a hyaluronic acid solution;

[0049] The hyaluronic acid solution is mixed with an amino-containing silane coupling agent to perform a first reaction to form an intermediate reactant;

[0050] The intermediate reactant is mixed with a catalyst to perform a second reaction to form silanized hyaluronic acid;

[0051] The bio-based solvent is glycerol and / or hexafluorophosphate ionic liquid; and the catalyst is a metal oxide supported by the ionic liquid.

[0052] The synthesis method of silylated hyaluronic acid provided in the present application adopts an amino-containing silane coupling agent as a modifier to achieve simultaneous amidation and silylation, thereby improving the degree and efficiency of modification and simplifying the synthesis steps; adopting bio-based solvents and environmentally friendly catalysts reduces the negative impact on the environment and improves the biocompatibility and safety of the product. The silylated hyaluronic acid synthesized in the present application has a high silicon content and is a water-soluble macromolecule, which can meet its application requirements in cosmetics, health products and pharmaceutical excipients.

[0053] In some embodiments, the amino-containing silane coupling agent includes N-(2-aminoethyl)-3-aminopropyltrimethoxysilane and / or 3-aminopropyltrimethoxysilane.

[0054] It is understandable that the amino-containing silane coupling agent contains both amino groups and siloxy groups, and its amino groups and the carboxyl groups of hyaluronic acid can be pre-activated to form amide bonds, while the remaining amino groups and hydroxyl groups can be used for subsequent silanization modification, thereby improving the modification degree and reaction efficiency.

[0055] In some embodiments, the hexafluorophosphate ionic liquid includes at least one of 1-butyl-3-methylimidazolium hexafluorophosphate, 1-propyl-3-methylimidazolium hexafluorophosphate, 1-ethyl-3-methylimidazolium hexafluorophosphate, 1,3-dimethylimidazolium hexafluorophosphate, and 1-hexyl-3-methylimidazolium hexafluorophosphate.

[0056] It can be understood that glycerol or hexafluorophosphate ionic liquids have good solubility in hyaluronic acid at room temperature and are inert systems. They will not participate in the modification reaction between hyaluronic acid and the amino-containing silane coupling agent. They can achieve a pre-activation (amide bond formation) reaction between the amino group of the amino-containing silane coupling agent and the carboxyl group of hyaluronic acid at room temperature, which is beneficial to control the reaction, improve the reaction efficiency, and is environmentally friendly.

[0057] In some embodiments, in the catalyst, the ionic liquid is a hexafluorophosphate ionic liquid, and the metal oxide includes ZrO 2 .

[0058] In the above solvent system, the metal oxide supported by the ionic liquid is used to catalyze the hydrolysis and condensation of the silyl group in the aminosilane coupling agent, while promoting the cross-linking between HA chains, thereby improving the degree of modification and the reaction efficiency.

[0059] Optionally, the mass volume ratio of the hyaluronic acid to the bio-based solvent is 1g:(30-60)mL, specifically 1g:30mL, 1g:35mL, 1g:40mL, 1g:45mL, 1g:50mL, 1g:55mL, 1g:60mL, etc.; the mass ratio of the hyaluronic acid to the amino-containing silane coupling agent is 1:(0.2-0.6), specifically 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, etc.; the mass ratio of the hyaluronic acid to the catalyst is 1:(0.05-0.2), specifically 1:0.05, 1:0.10, 1:0.15, 1:0.20, etc.

[0060] Optionally, the conditions of the first reaction include: reacting at room temperature for 1.5-4h; specifically, reacting at room temperature for 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, etc.; the conditions of the second reaction include: microwave power 200-500W, reaction temperature 50-75°C, reaction time 2-4h; specifically, microwave power can be 200W, 250W, 300W, 350W, 400W, 450W, 500W, etc.; reaction temperature can be 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, etc.; reaction time can be 2h, 2.5h, 3h, 3.5h, 4h, etc. In the second reaction, microwave technology is used to accelerate the reaction, shorten the synthesis cycle, and improve the reaction efficiency.

[0061] In some embodiments, the step of performing the second reaction further includes purification and drying steps to remove unreacted precursors and catalyst residues and ensure that the conductivity of the product meets the standard.

[0062] There is no special limitation on the purification or drying method, and the purification method may include dialysis and / or resin adsorption, etc., and the drying method may include at least one of natural drying, drying and freeze drying. For example, the dialysis uses an ultrafiltration membrane of 10000-15000Da, and specifically 10000Da, 11000Da, 12000Da, 13000Da, 14000Da, and 15000Da can be used; the freeze drying conditions include: the freeze drying temperature is -60~-40℃; the freeze drying time is 20-40h; specifically, the freeze drying temperature can be -60℃, -55℃, -50℃, -40℃, etc.; the freeze drying time can be 20h, 24h, 28h, 32h, 36h, 40h, etc.

[0063] The second aspect of the present application provides silanized hyaluronic acid synthesized by the aforementioned synthesis method.

[0064] The silanized hyaluronic acid synthesized in the present application has a high silicon content and is a water-soluble macromolecule. In some embodiments, the silicon content of the silanized hyaluronic acid is ≥4%.

[0065] The third aspect of the present application provides the use of the aforementioned silanized hyaluronic acid in cosmetics, health products and pharmaceutical excipients.

[0066] The silanized hyaluronic acid synthesized in the present application has a high silicon content and is a water-soluble macromolecule, which can meet the application requirements in cosmetics, health products and pharmaceutical excipients.

[0067] It is worth noting that the raw materials used in the examples of the present application are all common commercially available products, and their sources are not specifically limited.

[0068] The following is an exemplary description of some of the raw materials in the examples:

[0069] Catalyst: IL-ZrO 2 :1-Butyl-3-methylimidazolium hexafluorophosphate supported ZrO 2 , provided by Xi'an Qiyue Biotechnology Co., Ltd.;

[0070] Hyaluronic acid: average molecular weight 10,000, provided by Bloomage Biopharmaceuticals.

[0071] The following are specific embodiments.

[0072] Example 1

[0073] The synthesis method of silanized hyaluronic acid comprises the following steps:

[0074] 1) Dissolve 1g hyaluronic acid (HA) in 50ml glycerol solvent to form HA solution;

[0075] 2) Take 0.5 g of N-(2-aminoethyl)-3-aminopropyltrimethoxysilane (AEAPTMS) and add it to the above HA solution. Stir and react at room temperature for 2 hours to fully pre-activate the amino group of AEAPTMS and the carboxyl group of HA to form an amide bond, thereby obtaining an intermediate reactant;

[0076] 3) Add 0.1 g of ionic liquid-supported metal oxide (IL-ZrO 2 ) as a catalyst, the reaction system was placed in a microwave reactor, the microwave power was set to 300 W, the reaction temperature was set to 60°C, and the reaction time was set to 3 hours, to promote the hydrolysis and condensation of the silyl groups in AEAPTMS and promote the cross-linking between HA chains;

[0077] 4) After the reaction, an ultrafiltration membrane with a molecular weight cutoff of 10,000 Da was used to separate and purify the product to remove unreacted AEAPTMS and IL-ZrO 2 residue; the product solution was dialyzed with deionized water until the conductivity was less than 5μS / cm; the dialyzed solution was freeze-dried at -50°C for 24 hours to obtain a silanized hyaluronic acid product.

[0078] Example 2

[0079] The synthesis method of silanized hyaluronic acid comprises the following steps:

[0080] 1) 2 g of hyaluronic acid (HA) was dissolved in 80 ml of ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate ([Bmim][PF6]) solvent to form a HA solution;

[0081] 2) Take 1g of N-(2-aminoethyl)-3-aminopropyltrimethoxysilane (AEAPTMS) and add it to the HA solution. Stir and react at room temperature for 2.5 hours to fully pre-activate the amino group of AEAPTMS and the carboxyl group of HA to form an amide bond to obtain an intermediate reactant;

[0082] 3) Add 0.2 g of ionic liquid-supported metal oxide (IL-ZrO 2 ) as a catalyst; placing the reaction system in a microwave reactor, setting the microwave power to 350W, the reaction temperature to 65°C, and the reaction time to 3.5 hours, to promote the hydrolysis and condensation of the silyl groups in AEAPTMS and promote the cross-linking between HA chains;

[0083] 4) After the reaction, an ultrafiltration membrane with a molecular weight cutoff of 12000Da was used to separate and purify the product to remove unreacted AEAPTMS and IL-ZrO 2 residue; the product solution was dialyzed with deionized water until the conductivity was less than 4μS / cm; the dialyzed solution was freeze-dried at -45°C for 30 hours to obtain silanized hyaluronic acid.

[0084] Comparative Example 1

[0085] The experimental steps were similar to those of Example 2, except that 80 ml of the ionic liquid used to dissolve HA was replaced with water.

[0086] Comparative Example 2

[0087] The experimental steps were similar to those of Example 2, except that 80 ml of the ionic liquid ([Bmim][PF6]) used to dissolve HA was replaced with 1-ethyl-3-methylimidazolium acetate.

[0088] Comparative Example 3

[0089] The experimental steps are similar to those in Example 2, except that the metal oxide (IL-ZrO 2 ) was replaced with SiO supported by N-butylpyridinium hexafluorophosphate 2 (Produced by Xi'an Qiyue Biotechnology Co., Ltd.).

[0090] Test Case

[0091] 1. Infrared spectrum: The silanized hyaluronic acid of Example 1 was subjected to infrared (Fourier transform infrared spectrometer FT-IR) analysis. The results are shown in Figure 1 . Figure 1 Middle 942cm -1 and 886cm -1 The peak at is Si-CH 3 The vibration peak of , it can be seen that the silanization modification is successful and the structure of the prepared silanized sodium hyaluronate is correct.

[0092] 2. Silicon content: ICP test was performed on the silanized hyaluronic acid of the embodiment and comparative example. The results are shown in Table 1-2.

[0093] Table 1 ICP test results of silanized hyaluronic acid in Example 1

[0094]

[0095] Table 2 Silicon content of silanized hyaluronic acid in Examples and Comparative Examples

[0096]

[0097] It can be seen that the silanized hyaluronic acid of Example 1-2 has a higher silicon content, while the silicon content of the silanized hyaluronic acid prepared in Comparative Example 1-3 is greatly reduced. It can be seen that in the reaction system of the present application, the type of solvent and the type of catalyst have a greater impact on the reaction.

[0098] 3. Water solubility: The silylated hyaluronic acid prepared in Examples 1-2 was dissolved in water at a ratio of 1 g:99 mL to prepare an aqueous solution of silylated hyaluronic acid. The obtained aqueous solution of silylated hyaluronic acid was uniform and transparent. The appearance of the aqueous solution of silylated hyaluronic acid in Example 1 is shown in FIG. Figure 2 .

[0099] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0100] The above-mentioned embodiments only express several implementation methods of the present application, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for a person of ordinary skill in the art, several variations and improvements can be made without departing from the concept of the present application, and these all belong to the protection scope of the present application. Therefore, the protection scope of the patent of the present application shall be subject to the attached claims.

Claims

1. A method for synthesizing silanized hyaluronic acid, characterized in that: The steps include: dissolving hyaluronic acid in a bio-based solvent to form a hyaluronic acid solution; The hyaluronic acid solution is mixed with an amino-containing silane coupling agent to perform a first reaction to form an intermediate reactant; The intermediate reactant is mixed with a catalyst to perform a second reaction to form silanized hyaluronic acid; The bio-based solvent is glycerol and / or hexafluorophosphate ionic liquid; and the catalyst is a metal oxide supported by the ionic liquid.

2. The synthesis method according to claim 1, characterized in that The amino-containing silane coupling agent includes N-(2-aminoethyl)-3-aminopropyltrimethoxysilane and / or 3-aminopropyltrimethoxysilane.

3. The synthesis method according to claim 1, characterized in that The hexafluorophosphate ionic liquid includes at least one of 1-butyl-3-methylimidazolium hexafluorophosphate, 1-propyl-3-methylimidazolium hexafluorophosphate, 1-ethyl-3-methylimidazolium hexafluorophosphate, 1,3-dimethylimidazolium hexafluorophosphate and 1-hexyl-3-methylimidazolium hexafluorophosphate.

4. The synthesis method according to claim 1, characterized in that In the catalyst, the ionic liquid is a hexafluorophosphate ionic liquid, and the metal oxide includes ZrO2.

5. The synthesis method according to any one of claims 1 to 4, characterized in that The mass volume ratio of the hyaluronic acid to the bio-based solvent is 1 g: (30-60) mL; and / or the mass ratio of the hyaluronic acid to the amino-containing silane coupling agent is 1:(0.2-0.6); And / or the mass ratio of the hyaluronic acid to the catalyst is 1:(0.05-0.2).

6. The synthesis method according to any one of claims 1 to 4, characterized in that The conditions of the first reaction include: reacting at room temperature for 1.5-4h; The conditions of the second reaction include: microwave power of 200-500W, reaction temperature of 50-75°C, and reaction time of 2-4h.

7. The synthesis method according to any one of claims 1 to 4, characterized in that The step of performing the second reaction further includes the steps of purification and drying; Optionally, the purification comprises dialysis and / or resin adsorption; Optionally, the drying includes at least one of natural drying, oven drying and freeze drying.

8. The synthesis method according to claim 7, characterized in that The dialysis uses an ultrafiltration membrane of 10000-15000Da; the freeze-drying conditions include: the freeze-drying temperature is -60~-40°C; the freeze-drying time is 20-40h.

9. Silylated hyaluronic acid synthesized by the synthesis method according to any one of claims 1 to 8; Optionally, the silicon content of the silanized hyaluronic acid is ≥4%.

10. Use of the silanized hyaluronic acid according to claim 9 in cosmetics, health products and pharmaceutical excipients.

Images