A silylated hyaluronic acid, its synthesis method and application

Abstract

The present application discloses a silylated hyaluronic acid, its synthesis method and application, belonging to the technical field of biomaterial synthesis. The synthesis method of the silylated 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 to carry out a first reaction to form an intermediate reactant; mixing the intermediate reactant with a catalyst to carry out a second reaction to form the silylated hyaluronic acid; the bio-based solvent is glycerol and / or hexafluorophosphate-based ionic liquid; the catalyst is an ionic liquid-supported metal oxide. The present application provides an environmentally friendly and efficient synthesis method of silylated hyaluronic acid. The synthesized silylated hyaluronic acid has a high silicon content and is a water-soluble macromolecule, which can meet the application requirements in cosmetics, health products and pharmaceutical excipients.

Description

Technical Field

[0001] This application relates to the technical field of biomaterial synthesis, and particularly to a silanized hyaluronic acid and its synthesis method and application. Background Art

[0002] Hyaluronic acid (HA), also known as hyaluronic acid, is a natural high-molecular mucopolysaccharide formed by the repeated connection of N-acetylglucosamine and D-glucuronic acid disaccharide units. It belongs to natural high-molecular non-sulfated glycosaminoglycans and has excellent water solubility and biodegradability. It is widely distributed in the extracellular matrix of soft connective tissues of humans and animals and has various important physiological functions, such as maintaining the extracellular space, regulating osmotic pressure, lubrication, etc. In terms of wound healing, HA can regulate cell adhesion, migration, differentiation, and proliferation, reduce the inflammatory response, and also has the characteristics of improving cell infiltration, scavenging free radicals, and antioxidant properties. 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, due to its high hydrophilicity, it has poor lipophilicity, resulting in problems such as too short half-life, fast degradation rate in the body, and short in-situ residence time, resulting in low bioavailability. However, the HA structure contains chemical active sites such as hydroxyl groups 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 performance, no cytotoxicity, no skin irritation, and can promote the proliferation of keratinocytes, and can be used to prepare cosmetics and pharmaceutical excipients with skin moisturizing and repair functions.

[0004] A method has been disclosed in which a hyaluronic acid solution and a sodium silanol solution are mixed and reacted, and then the pH is adjusted 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. A method for preparing silanized hyaluronic acid has been disclosed, but the reaction raw material chlorosilane in this method is very sensitive to water, decomposes rapidly when encountering water, forms smoke during the dropping process, and decomposes to generate hydrochloric acid, which has strong corrosiveness. Therefore, there are strict requirements for its storage and use, and this 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), and the performance of hyaluronic acid cannot be effectively improved; 2) When the degree of silanization is relatively high, the cross-linking degree of the prepared silanized hyaluronic acid is too high and it cannot be dissolved in water, and can only be used for hydrogel products, which limits its application.

[0006] Based on the above situation, developing 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 object of this 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, is a water-soluble macromolecule, and has broad application prospects.

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

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

[0010] Mix the hyaluronic acid solution with an amino-containing silane coupling agent for a first reaction to form an intermediate reactant;

[0011] Mix the intermediate reactant with a catalyst for a second reaction to form silanized hyaluronic acid;

[0012] The bio-based solvent is glycerol and / or hexafluorophosphate ionic liquid; the catalyst is a metal oxide supported by an 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 ZrO2.

[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-group-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 for the first reaction include: reacting at room temperature for 1.5 - 4 h;

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

[0021] In some embodiments, after the step of performing the second reaction, there are further steps of purification and drying.

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

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

[0024] In some embodiments, the dialysis uses an ultrafiltration membrane with a molecular weight cut-off of 10000 - 15000 Da.

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

[0026] In the second aspect of the present application, there is provided a silylated hyaluronic acid synthesized by the aforementioned synthesis method.

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

[0028] In the third aspect of the present application, there is provided the application of the aforementioned silylated hyaluronic acid in cosmetics, health products, and pharmaceutical excipients.

[0029] Advantages of the present application:

[0030] 1. The present application provides an environmentally friendly and efficient synthesis method for silylated hyaluronic acid. By using an amino-group-containing silane coupling agent as a modifier, the simultaneous progress of amidation and silylation is achieved, improving the degree and efficiency of modification and simplifying the synthesis steps; by using a bio-based solvent and an environmentally friendly catalyst, the negative impact on the environment is reduced, and the biocompatibility and safety of the product are enhanced.

[0031] 2. The silylated 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 will briefly introduce the drawings required for the description of the embodiments or the prior art. The drawings are only for the purpose of showing the preferred embodiments and are not considered to limit the present application. Throughout the drawings, the same reference numerals are used to represent the same components. In the drawings:

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

[0034] Figure 2 Appearance diagram of the aqueous solution of the silanized hyaluronic acid in Example 1. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0035] To make the objectives, technical solutions, and advantages of the present application clearer and the understanding of the disclosed content of the present application more thorough and comprehensive, the following will clearly and completely describe the technical solutions of the present application in combination with the specific embodiments of the present application and the corresponding drawings. The described embodiments are only a part of the embodiments of the present application, rather than all of the embodiments.

[0036] The following will give a detailed description of the implementation of the present application in combination with the drawings. This embodiment is implemented on the premise of the technical solution of the present application, and the detailed implementation manners and specific operation processes 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 commonly understood by those skilled in the technical field to which this application belongs. The terms used in the specification of this application are only for the purpose of describing specific embodiments and are not intended to limit this application.

[0038] TERMS

[0039] Unless otherwise stated or there are contradictions, the terms or phrases used herein have the following meanings:

[0040] In the present application, when it comes to "multiple", "a variety of", etc., unless otherwise specified, it means greater than 2 or equal to 2 in quantity. For example, "one or more", "at least one" means one or greater than or equal to two.

[0041] In the present application, "further", "especially", etc. are used for descriptive purposes and represent differences in content, but should not be construed as limiting the protection scope of the present application.

[0042] In the present application, among the technical features described in an open-ended manner, it includes a closed technical solution composed of the listed features, and also includes an open technical solution containing the listed features.

[0043] In this application, when it comes to numerical intervals (i.e., numerical ranges), unless otherwise specified, the distribution of the selectable numerical values within the numerical interval is considered continuous, and includes the two numerical endpoints of the numerical interval (i.e., the minimum value and the maximum value), as well as each numerical value between these two numerical endpoints. Unless otherwise specified, when the numerical interval only refers to the integers within the numerical interval, it includes the two endpoint integers of the numerical range, as well as each integer between the two endpoints, which is equivalent to directly listing each integer. When providing multiple numerical ranges to describe features or characteristics, these numerical ranges can be combined. In other words, unless otherwise specified, the numerical ranges disclosed herein should be understood to include any and all sub-ranges subsumed therein. The "numerical values" in the numerical interval can be any quantitative values, such as numbers, percentages, ratios, etc. The "numerical interval" allows for a broad inclusion of numerical interval types such as percentage intervals, ratio intervals, ratio value intervals, etc.

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

[0045] In this application, unless otherwise specifically limited, the temperature parameter allows for both constant temperature treatment and variation within a certain temperature interval. It should be understood that the constant temperature treatment allows the temperature to fluctuate within the accuracy range controlled by the instrument. Fluctuations within ranges such as ±5 °C, ±4 °C, ±3 °C, ±2 °C, and ±1 °C are allowed.

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

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

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

[0049] Mix the hyaluronic acid solution with an amino - containing silane coupling agent to carry out a first reaction to form an intermediate reactant;

[0050] Mix the intermediate reactant with a catalyst to carry out a second reaction to form silanized hyaluronic acid;

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

[0052] The synthesis method of the silanized hyaluronic acid provided by this application uses an amino-containing silane coupling agent as a modifier to achieve the simultaneous progress of amidation and silanization, improve the modification degree and efficiency, and simplify the synthesis steps; uses a bio-based solvent and an environmentally friendly catalyst to reduce the negative impact on the environment and enhance the biocompatibility and safety of the product. The silanized hyaluronic acid synthesized in this 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.

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

[0054] It can be understood that the amino-containing silane coupling agent contains both an amino group and a silaneoxy group. Its amino group and the carboxyl group of hyaluronic acid can form an amide bond through pre-activation, and the remaining amino group and hydroxyl group 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 liquid has good solubility in hyaluronic acid at room temperature and is an inert system that does not participate in the modification reaction between hyaluronic acid and the amino-containing silane coupling agent. It can achieve the pre-activation (formation of an amide bond) 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 controlling the reaction, improving the reaction efficiency, and is green and friendly.

[0057] In some embodiments, in the catalyst, the ionic liquid is a hexafluorophosphate ionic liquid, and the metal oxide includes ZrO2.

[0058] In the above solvent system, an ionic liquid-supported metal oxide is used to catalyze the hydrolysis and condensation of the silyl group in the amino silane coupling agent, and at the same time promote the cross-linking between HA chains, improving the modification degree and reaction efficiency.

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

[0060] Optionally, the conditions for the first reaction include: reacting at room temperature for 1.5 - 4 h; specifically, it can be reacting at room temperature for 1.5 h, 2 h, 2.5 h, 3 h, 3.5 h, 4 h, etc.; the conditions for the second reaction include: microwave power of 200 - 500 W, reaction temperature of 50 - 75 °C, and reaction time of 2 - 4 h; specifically, the microwave power can be 200 W, 250 W, 300 W, 350 W, 400 W, 450 W, 500 W, etc.; the reaction temperature can be 50 °C, 55 °C, 60 °C, 65 °C, 70 °C, 75 °C, etc.; the reaction time can be 2 h, 2.5 h, 3 h, 3.5 h, 4 h, 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, after the step of performing the second reaction, purification and drying steps are further included. Unreacted precursors and catalyst residues are removed through purification, and the conductivity of the product meets the standard.

[0062] There is no particular limitation on the method of purification or drying. The method of purification can include dialysis and / or resin adsorption, etc., and the method of drying can include at least one of natural drying, baking, and freeze-drying. For example, the dialysis uses an ultrafiltration membrane with a molecular weight cut-off of 10000 - 15000 Da, specifically, it can be 10000 Da, 11000 Da, 12000 Da, 13000 Da, 14000 Da, 15000 Da; the conditions for freeze-drying include: freeze-drying temperature of -60 ~ -40 °C; freeze-drying time of 20 - 40 h; specifically, the freeze-drying temperature can be -60 °C, -55 °C, -50 °C, -40 °C, etc.; the freeze-drying time can be 20 h, 24 h, 28 h, 32 h, 36 h, 40 h, etc.

[0063] In the second aspect of the present application, a silylated hyaluronic acid synthesized by the aforementioned synthesis method is provided.

[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-ZrO2: 1-butyl-3-methylimidazolium hexafluorophosphate supported ZrO2, 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-loaded metal oxide (IL-ZrO2) as a catalyst to the intermediate reactant, place the reaction system in a microwave reactor, set the microwave power to 300 W, the reaction temperature to 60 ° C, and the reaction time 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 is completed, ultrafiltration with a molecular weight cut-off of 10,000 Da is used to separate and purify the product, removing unreacted AEAPTMS and IL-ZrO2 residues; the product solution is dialyzed with deionized water until the conductivity is less than 5 μS / cm; the dialyzed solution is freeze-dried at -50 °C for 24 hours to obtain the silylated hyaluronic acid product.

[0078] Example 2

[0079] A method for synthesizing silylated hyaluronic acid comprises the following steps:

[0080] 1) Take 2 g of hyaluronic acid (HA) and dissolve it in 80 ml of the ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate ([Bmim][PF6]) solvent to form an HA solution;

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

[0082] 3) Add 0.2 g of ionic liquid-supported metal oxide (IL-ZrO2) as a catalyst to the intermediate reactant; place the reaction system in a microwave reactor, set the microwave power to 350 W, the reaction temperature to 65 °C, and the reaction time to 3.5 hours to promote the hydrolysis and condensation of the silyl group in AEAPTMS and at the same time promote the cross-linking between HA chains;

[0083] 4) After the reaction is completed, ultrafiltration with a molecular weight cut-off of 12,000 Da is used to separate and purify the product, removing unreacted AEAPTMS and IL-ZrO2 residues; the product solution is dialyzed with deionized water until the conductivity is less than 4 μS / cm; the dialyzed solution is freeze-dried at -45 °C for 30 hours to obtain silylated hyaluronic acid.

[0084] Comparative Example 1

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

[0086] Comparative Example 2

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

[0088] Comparative Example 3

[0089] The experimental steps were similar to those of Example 2, except that the metal oxide (IL-ZrO2) supported by the ionic liquid was replaced with SiO2 supported by N-butylpyridinium hexafluorophosphate (provided 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 the vibration peak of Si-CH3, which shows 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-described embodiments merely represent several implementation manners of the present application. The description is relatively specific and detailed, but it should not be construed as a limitation on the scope of the invention patent. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present application, several modifications and improvements can still be made, and these all fall within the protection scope of the present application. Therefore, the protection scope of the patent of the present application shall be subject to the appended claims.

Claims

1. A method for synthesizing silanized hyaluronic acid, characterized in that, It includes the following steps: Dissolve hyaluronic acid in a bio-based solvent to form a hyaluronic acid solution; Mix the hyaluronic acid solution with an amino-containing silane coupling agent to carry out a first reaction to form an intermediate reactant; Mix the intermediate reactant with a catalyst to carry 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-supported metal oxide; In the catalyst, the ionic liquid is a hexafluorophosphate ionic liquid, and the metal oxide includes ZrO2; The mass-volume ratio of the hyaluronic acid to the bio-based solvent is 1 g:(30 - 60) mL; The mass ratio of the hyaluronic acid to the amino-containing silane coupling agent is 1:(0.2 - 0.6); The mass ratio of the hyaluronic acid to the catalyst is 1:(0.05 - 0.2); The conditions of the first reaction include: reacting at room temperature for 1.5 - 4 h; The conditions of the second reaction include: microwave power of 200 - 500 W, reaction temperature of 50 - 75 °C, and reaction time of 2 - 4 h.

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, wherein, 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 any one of claims 1-3, characterized in that, After the step of carrying out the second reaction, it further includes the steps of purification and drying; The purification includes dialysis and / or resin adsorption; The drying includes at least one of natural drying, drying in an oven, and freeze-drying.

5. The synthesis method according to claim 4, characterized in that, The dialysis uses an ultrafiltration membrane with a molecular weight cut-off of 10000 - 15000 Da; the conditions of the freeze-drying include: freeze-drying temperature of -60 to -40 °C; freeze-drying time of 20 - 40 h.

6. Silanized hyaluronic acid synthesized by the synthesis method according to any one of claims 1 - 5; The silicon content of the silanized hyaluronic acid is ≥4%.

7. Use of the silanized hyaluronic acid according to claim 6 in cosmetics, health products, and pharmaceutical excipients.

Images