A sodium hyaluronate gel and its preparation method

Abstract

This application provides a sodium hyaluronate gel and its preparation method, belonging to the field of biomedical materials, aiming to solve the problem of severe performance degradation of cross-linked sodium hyaluronate gels during moist heat sterilization. The gel contains cross-linked sodium hyaluronate and is compounded with a solvation shell-building agent and a high-temperature free radical scavenger. These two agents synergistically constitute a dual protection system, jointly protecting the gel structure. The preparation method includes matrix cross-linking, in-situ loading of the protection system through dialysis equilibrium, homogenization, and terminal moist heat sterilization. After moist heat sterilization at 121°C, the gel of this invention exhibits a high storage modulus retention rate, demonstrating excellent thermal stability and synergistic effects, ensuring stable product performance.

Description

Technical Field

[0001] This application belongs to the field of biomedical materials technology, specifically relating to a sodium hyaluronate cross-linked gel. Background Technology

[0002] Sodium hyaluronate, also known as hyaluronic acid, is a naturally occurring polysaccharide in the human body. Due to its excellent biocompatibility and water-retention properties, sodium hyaluronate is widely used to prepare cross-linked gels for use as a dermal filler in the medical aesthetics field or as a joint lubricant in orthopedics.

[0003] As implantable medical devices, these cross-linked sodium hyaluronate gel products must undergo terminal sterilization before being marketed to meet the sterility assurance levels required by regulations. Among these methods, moist heat sterilization, such as autoclaving at 121°C, is one of the most commonly used and reliable sterilization methods.

[0004] However, existing technologies face an irreconcilable technical contradiction: the conflict between the reliability of sterilization and the integrity of product performance. Sodium hyaluronate is a heat-sensitive polymer. In a high-temperature, high-pressure aqueous environment, the glycosidic bonds on its molecular backbone are easily hydrolyzed and broken. Simultaneously, the cross-linking bonds used to construct the three-dimensional gel network may also break. This leads to a sharp decrease in the average molecular weight of the gel, macroscopically manifested as a significant drop in the gel's viscoelasticity and supporting forces (such as storage modulus G'). The gel may even change from a "gel-like" state to a "liquid" state, completely losing its intended function. This degradation not only causes large batch-to-batch performance fluctuations but also severely affects the product's shelf-life stability.

[0005] To address this issue, existing technologies have attempted to add protective agents to the gel, such as polyols like mannitol or single-function antioxidants, to slow down degradation. However, these approaches offer limited protection, and under harsh 121°C moist heat sterilization conditions, the loss of gel performance remains high, failing to fundamentally solve the problem. Therefore, developing a cross-linked sodium hyaluronate gel capable of withstanding terminal moist heat sterilization while maximally preserving its original high molecular weight and excellent rheological properties remains a pressing technical challenge in this field. Summary of the Invention

[0006] The purpose of this application is to solve the technical problem that the performance of cross-linked sodium hyaluronate gel is severely degraded during terminal moist heat sterilization in the prior art, and to provide a sodium hyaluronate gel and its preparation method. After undergoing high temperature moist heat sterilization, the gel can retain its original molecular weight and viscoelasticity and other key properties to the maximum extent.

[0007] To achieve the above objectives, this application provides a sodium hyaluronate gel, characterized in that the gel comprises: cross-linked sodium hyaluronate, a solvated shell building agent, and a high-temperature free radical scavenger; the total weight percentage of the solvated shell building agent and the high-temperature free radical scavenger is 0.1% to 1.0%; the solvated shell building agent is selected from at least one of ectoine or an amphiphilic trehalose derivative; and the high-temperature free radical scavenger is selected from at least one of carnosine or ferulic acid.

[0008] In a preferred embodiment of this application, the solvation shell builder is ectoine, and the high-temperature free radical scavenger is carnosine.

[0009] Furthermore, the trehalose derivative is selected from trehalose dipalmitate.

[0010] Furthermore, the cross-linked sodium hyaluronate has a weight percentage content of 1.5% to 3.0%.

[0011] Furthermore, the cross-linked sodium hyaluronate is obtained by cross-linking with 1,4-butanediol diglycidyl ether as a cross-linking agent.

[0012] Optionally, the gel may also contain lidocaine hydrochloride.

[0013] Optionally, the solvation shell builder is ectoine, and the high-temperature free radical scavenger is carnosine; and the gel is in Moist heat sterilization Minutes later, energy storage modulus Retention rate .

[0014] This application also provides a method for preparing sodium hyaluronate crosslinked gel according to any one of the above claims, characterized by comprising the following steps: S1: reacting sodium hyaluronate with a crosslinking agent to obtain a crude crosslinked gel; S2: placing the crude crosslinked gel in a buffer solution containing a solvation shell-building agent and a high-temperature free radical scavenger for dialysis equilibration, so as to load the solvation shell-building agent and the high-temperature free radical scavenger into the gel network; wherein, the dialysis equilibration temperature is... to The time is at least S2: After homogenizing the gel obtained in step S2, perform terminal moist heat sterilization.

[0015] Optionally, the terminal moist heat sterilization is performed at a temperature of 121°C.

[0016] Compared with the prior art, this application has the following beneficial effects: 1. Significantly improved thermal stability of the gel, achieving near-non-destructive retention of performance. The gel provided in this application, after undergoing terminal moist heat sterilization at 121℃, retains up to 96.5% of its storage modulus G' and 94.2% of its weight-average molecular weight Mw, far exceeding the performance of solutions using existing protective agents. This achieves a high degree of consistency in key product performance before and after sterilization, ensuring stable and reliable clinical application results.

[0017] 2. Experiments have shown that the protective effect of using solvated shell building agents or high-temperature free radical scavengers alone is limited. However, when the two are used in combination as described in this application, the protective effect is much greater than the simple sum of the effects of the two alone, showing a synergistic effect. This synergistic mechanism has not been revealed in the prior art.

[0018] 3. This invention has determined the optimal concentration range of key modifiers through experiments. This range is the best balance window that takes into account both high protection efficiency and product safety, avoiding the problem of insufficient protection due to too low a concentration or adverse side effects such as yellowing of the product due to too high a concentration. This proves that the numerical range defined by this invention is obtained through creative labor. Attached Figure Description

[0019] To more clearly illustrate the technical solutions in the embodiments of this application or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0020] Figure 1 This is a schematic flowchart illustrating a method for preparing sodium hyaluronate gel, as provided in an embodiment of this application.

[0021] Key reference numerals: S10: Matrix crosslinking network construction step; S20: Purification and in-situ loading step; S30: Homogenization and terminal sterilization step. Detailed Implementation

[0022] To make the objectives, technical solutions, and advantages of this application clearer, the following will provide a more detailed description of this application in conjunction with the accompanying drawings and specific embodiments. It should be noted that the specific embodiments described herein are merely illustrative of this application and are not intended to limit the scope of protection of this application.

[0023] Example 1 This embodiment provides a sodium hyaluronate gel and its preparation method. In addition to containing a cross-linked sodium hyaluronate matrix, the gel incorporates a dual-protection system consisting of a solvation shell builder and a high-temperature free radical scavenger. In one embodiment of this application, ectoine is preferably used as the solvation shell builder, and carnosine is used as the high-temperature free radical scavenger.

[0024] Please see Figure 1 This is a schematic diagram of the overall process of the preparation method described in this embodiment. Specifically, the method mainly includes a matrix crosslinking network construction step S10, a purification and in-situ loading step S20, and a homogenization and terminal sterilization step S30.

[0025] First, step S10, the matrix crosslinking network construction step, is performed to construct the three-dimensional network framework of the gel. The necessary raw materials are prepared, including: a weight-average molecular weight of 2.0 × 10⁻⁶. 6 Dalton sodium hyaluronate powder (purchased from Bloomage Biotechnology, food grade), 1,4-butanediol diglycidyl ether (purchased from Sigma-Aldrich, purity >95%), sodium hydroxide (analytical grade), ectoine (purchased from Merck, purity >99%), carnosine (purchased from Yuanye Biotechnology, purity >99%), and phosphate buffer (pH 7.4) were used as the reaction medium. 1000 mL of a 0.25 mol / L sodium hydroxide aqueous solution was added to a 1.5 L stainless steel reactor equipped with a temperature-controlled jacket and a low-speed stirrer. The stirrer was started and set to 70 rpm, maintaining the reactor temperature at 45 °C. Then, 20 g of sodium hyaluronate powder was slowly added to the alkaline solution. Under continuous stirring at 45 °C, the sodium hyaluronate was allowed to fully swell and dissolve for approximately 4 hours, until a clear, transparent, homogeneous, viscous solution free of visible particles or clumps was formed. Understandably, sodium hyaluronate hydrates under alkaline conditions, allowing its molecular chains to fully extend, which is beneficial for the uniformity of subsequent cross-linking reactions. Subsequently, under conditions of maintaining 45°C and stirring at 70 rpm, 1.33 g of 1,4-butanediol diglycidyl ether was added to the reactor, with a cross-linking agent to sodium hyaluronate mass ratio of approximately 1:15. As a diepoxide compound, 1,4-butanediol diglycidyl ether's epoxy groups at both ends can undergo ring-opening etherification with the hydroxyl groups on the sodium hyaluronate molecular chains under alkaline catalysis, thereby forming stable ether bonds between different sodium hyaluronate molecular chains to construct a three-dimensional cross-linked network. This cross-linking reaction was carried out at 45°C for 7 hours. The relatively mild temperature of 45°C was chosen to ensure a sufficient reaction rate while minimizing thermal degradation of sodium hyaluronate during the reaction. After the reaction, a monolithic, elastic hydrogel was formed in the reactor, which is the coarse cross-linked gel.

[0026] Next, purification and in-situ loading step S20 is performed. The purpose of this step is to simultaneously achieve gel purification and efficient, uniform loading of the thermal stability protection system. The blocky coarse cross-linked gel obtained in step S10 is removed from the reactor and mechanically crushed through a 20-mesh stainless steel sieve into gel particles with a particle size of approximately 0.85 mm. This crushing operation increases the contact area between the gel and the subsequent dialysis solution, thereby significantly improving mass transfer efficiency. Subsequently, the dialysis equilibration solution is prepared. In a 15-liter container, 10 liters of phosphate buffer with a pH of 7.2 are added, and then 50 g of ectoine and 30 g of carnosine are dissolved sequentially under stirring, so that the final weight percentage concentrations of ectoine and carnosine in the dialysis solution reach 0.5% and 0.3%, respectively. The prepared gel particles are loaded into dialysis bags and completely immersed in the aforementioned dialysis equilibration solution containing ectoine and carnosine. Dialysis equilibration is performed at room temperature (25°C) for a total time of 24 hours. During this period, to maintain a sufficiently large concentration gradient between the inner and outer dialysate solutions to ensure purification and loading efficiency, a fresh equilibration solution containing the same concentration of protective agent was replaced every 8 hours. It is understood that two parallel mass transfer processes occur during dialysis. First, small molecule impurities such as unreacted 1,4-butanediol diglycidyl ether, sodium hydroxide, and reaction byproducts remaining inside the gel network diffuse continuously into the outer dialysate due to the concentration difference between the inside and outside of the gel, thus purifying the gel. Second, ectoine and carnosine molecules in the dialysate, driven by osmotic pressure, permeate backward and uniformly into the pores of the sodium hyaluronate cross-linked network, thereby completing the "in-situ loading" of the dual-protection system. After dialysis, the gel particles are removed, and the pH value of the outer dialysate is monitored using a precision pH meter. When it stabilizes within the range of 7.2 ± 0.2, it indicates that the gel has reached neutrality, and the purification process is complete.

[0027] Subsequently, homogenization and terminal sterilization step S30 is performed. This step aims to process the gel particles into a uniform shape suitable for injection and complete the final sterilization process. The gel particles obtained in step S20, which have successfully incorporated the dual-protection system, are collected and transferred to a high-speed shear homogenizer. The shear rate is set to 8000 rpm, and homogenization is performed for 5 minutes until the high-speed shear force further breaks down and mixes the gel particles, forming a uniform, smooth, and particle-free paste-like gel. The homogenized gel is then precisely dispensed into 1 ml borosilicate glass syringes using an automated filling device and sealed with halogenated butyl rubber stoppers. Finally, the packaged syringes are neatly arranged on a tray in a high-pressure steam sterilizer, and the sterilization program is initiated. The temperature and pressure inside the sterilizer are raised to 121°C and 103 kPa, respectively, and maintained under these conditions for 20 minutes of moist heat sterilization. These conditions are standard for terminal sterilization of medical devices and effectively kill microorganisms to achieve the sterility assurance level required by regulations. After the sterilization process, to avoid potential changes in material properties caused by a sudden drop in temperature, a programmed cooling method was used to cool the product to room temperature at a rate of 3°C per minute. The final product obtained is a colorless, clear, uniform, and stable sodium hyaluronate cross-linked gel.

[0028] As an optional approach, to reduce pain during product injection and improve patient comfort, a local anesthetic can be added during the homogenization and terminal sterilization step S30. Specifically, lidocaine hydrochloride can be added to the gel during high-speed shear homogenization, ensuring it reaches a weight percentage of 0.3% in the final gel, and ensuring it is thoroughly mixed with the gel before dispensing and terminal sterilization.

[0029] Example 2 This embodiment includes multiple comparative examples, which are intended to compare the performance with the solution of this application to verify the significant technical progress achieved by the dual protection system proposed in this application compared with the prior art and single-component solutions, and to reveal its synergistic effect.

[0030] In this embodiment, five groups of gels were prepared, and the specific groupings are as follows: 1. The present invention group: prepared entirely according to the method of Example 1, the protective system being a complex of 0.5% ectoine and 0.3% carnosine.

[0031] 2. Comparative Example 1 (Blank Control Group): The preparation method was basically the same as in Example 1, but in the purification and in-situ loading step S20, pure phosphate buffer (pH 7.2) without any protective agent was used for dialysis.

[0032] 3. Comparative Example 2 (Prior Art Control Group): The preparation method was basically the same as in Example 1, but in the purification and in-situ loading step S20, dialysis was performed using phosphate buffer containing 0.8% mannitol. Mannitol is a commonly used heat protectant in the prior art.

[0033] 4. Comparative Example 3 (Single-component control A): The preparation method is basically the same as that in Example 1, but in the purification and in-situ loading step S20, dialysis is performed using phosphate buffer containing only 0.5% ectoine.

[0034] 5. Comparative Example 4 (Single-component control B): The preparation method is basically the same as that in Example 1, but in the purification and in-situ loading step S20, dialysis is performed using phosphate buffer containing only 0.3% carnosine.

[0035] For the five groups of gels mentioned above, performance tests were conducted before and after moist heat sterilization at 121℃. All tests were repeated three times, and the average value was taken. Storage modulus (G') was measured using a TADHR-2 rotational rheometer at 25℃, an oscillation frequency of 1 Hz, and a strain of 1%. G' is a key indicator for evaluating the elasticity and support capacity of the gel. The formula for calculating G' retention rate is: Determination of weight-average molecular weight (Mw): Determined using gel permeation chromatography-multi-angle laser light scattering. Mw reflects the integrity of the sodium hyaluronate molecular chain. The formula for calculating the Mw retention rate is: Color (b-value) detection: Measured using a colorimeter. The b-value reflects the yellowness of the gel; a higher value indicates a more yellow color.

[0036] The test results are summarized in the table below: The data in the table above clearly shows that: 1. The G' retention rate (96.5%) and Mw retention rate (94.2%) of the group of this invention are significantly higher than those of all comparative examples. This indicates that the gel provided by this application has excellent thermal stability, and after undergoing rigorous 121°C moist heat sterilization, its key physical properties and chemical structure are almost undamaged, achieving near-perfect retention of performance.

[0037] 2. Compared with Comparative Example 1 (blank control group), the G' retention rate of the present invention group increased by more than 54 percentage points and the Mw retention rate increased by nearly 60 percentage points, which fully demonstrates the effectiveness of the dual protection system.

[0038] 3. Compared with Comparative Example 2 (prior technology control group), the G' retention rate of the present invention group is 22 percentage points higher, which proves that the present application scheme has significant technical progress compared with the prior art using mannitol.

[0039] 4. It is particularly noteworthy that the effects of this invention exhibit an unexpected synergistic effect. The G' retention rates of Comparative Example 3 (using only ectoine) and Comparative Example 4 (using only carnosine) were 81.0% and 65.2%, respectively. If the protective effects of the two were simply additive, the high retention rate of 96.5% of this invention would not be explainable. It can be considered that this "1+1>2" synergistic effect stems from the organic combination of two mechanisms: physical barrier (solvation shell) and chemical scavenging (free radical capture), which produces a comprehensive protective effect far exceeding the sum of the individual effects of each component. It is understood that this synergistic protective mechanism has not been revealed in the prior art, and therefore possesses outstanding inventiveness.

[0040] Furthermore, to further verify the protective effect of the proposed solution on the gel microstructure, the gels of the present invention group (Example 1) and Comparative Example 1 (blank control group) were freeze-dried after sterilization, and their cross-sectional micromorphology was observed using a scanning electron microscope. The observation results showed that the gel of the present invention group exhibited a complete, uniform, and smooth honeycomb porous network structure with a uniform pore size distribution, mostly between 50-200 micrometers, and no obvious structural collapse or pore wall rupture was observed. This directly demonstrates that under the protection of the dual-protection system of this application, the three-dimensional network skeleton of the gel remained intact under the severe test of high-temperature and moist heat sterilization, which is the structural basis for the preservation of its macroscopic mechanical properties (such as G'). In contrast, the gel of Comparative Example 1 had its internal structure severely damaged; most of the original porous network collapsed, the pore walls ruptured and fused, forming cavities of extremely uneven sizes and dense collapsed areas. This indicates that without protection, the microstructure of conventional cross-linked sodium hyaluronate gel would be severely damaged during moist heat sterilization, leading to a sharp loss of macroscopic properties.

[0041] Example 3 This embodiment aims to demonstrate the scientific validity and necessity of the protective agent concentration range defined in this application by screening key modifiers of different concentrations, that is, the best balance between protective effect and product safety can be achieved within this range.

[0042] Following the preparation method described in Example 1, the following four groups of gels were prepared, differing only in the concentration of the protective agent in the dialysis equilibration solution used in the purification and in-situ loading step S20: 1. Low concentration group: The dialysate contains 0.1% ectoine and 0.1% carnosine (total concentration is 0.2%).

[0043] 2. Preferred concentration group: namely Example 1, the dialysate contains 0.5% ectoine and 0.3% carnosine (total concentration is 0.8%).

[0044] 3. High concentration group: The dialysate contains 1.0% ectoine and 0.5% carnosine (total concentration is 1.5%).

[0045] 4. Out-of-range group: The dialysate contains 5.0% ectoine (total concentration is 5.0%).

[0046] After sterilization at 121℃, the G' retention rate, Mw retention rate, and color b* value of each group of gels were measured. The results are shown in the table below: From the data in the table above, we can conclude that: When the total concentration of the key modifier increases from 0.2% to 1.5% (covering the preferred total content range of 0.1% to 1.0%), the G' retention rate and Mw retention rate of the gel remain at extremely high levels of over 88.0% and 85.5% respectively, and the color b value is below 2.5. The product has a clear and transparent appearance or only very slight color change, and the product has a clear and transparent appearance, which meets the application requirements.

[0047] When the total concentration of the protective agent is too high, for example, reaching 5.0% in the out-of-range group, although its G' retention rate and Mw retention rate are still high (90.0% and 88.0%, respectively), its color b* value rises sharply to 8.5, and the product appearance exhibits a distinct yellow tint. This yellowing may be attributed to the Maillard reaction or self-degradation of the excessive protective agent (especially amino acids) at high temperatures, which seriously affects the product's appearance quality and potential biosafety, resulting in the product's appearance and quality failing to meet application requirements.

[0048] Therefore, the range of 0.1% to 1.0% by weight of the key modifier proposed in this application defines a technical window that balances "high protective efficiency" and "product appearance safety." It is understandable that this range was not determined by chance, but rather through inventive experimentation, screening, and optimization, and thus has critical significance.

[0049] Experimental results show that when ectoine and carnosine are in to When combined within a specific total concentration range, the hydrated shell constructed by ectoine effectively blocks the attack of high-temperature water molecules, while carnosine scavenge the small number of free radicals that penetrate the shell. This dual mechanism of 'physical barrier + chemical scavenging' produces a non-linear synergistic effect at the microscopic level, thereby achieving... Retention rate from single component leap to above.

[0050] Example 4 This embodiment aims to verify the universality of the core technical concept of this application, that is, using the alternative materials disclosed in this application (such as a derivative of trehalose and ferulic acid) as components of the dual protection system can also achieve the beneficial effects of this application.

[0051] In this application, 'trehalose derivatives' preferably refer to esterified derivatives with an amphiphilic structure. These molecules can orient themselves around the sodium hyaluronate molecular chain, with their hydrophobic ends repelling hot water molecules and their hydrophilic ends binding to the sugar chain, thereby forming a denser solvated protective shell. For example, trehalose dipalmitate was used in Example 4.

[0052] In this embodiment, the solvation shell building agent is a derivative of trehalose, namely trehalose dipalmitate; the high-temperature free radical scavenger is ferulic acid. The preparation method basically follows the process of Example 1. Specifically, in the purification and in-situ loading step S20, the components of the dialysis equilibration solution are replaced with: 60 g of trehalose dipalmitate (to a final concentration of 0.6%) and 20 g of ferulic acid (to a final concentration of 0.2%) dissolved in 10 L of phosphate buffer with a pH of 7.2. Trehalose dipalmitate, as an amphiphilic molecule, can also form an effective physical protective layer around the sodium hyaluronate molecular chain; while ferulic acid, as a phenolic acid antioxidant, has excellent free radical scavenging ability. The remaining steps, including the matrix crosslinking network construction step S10 and the homogenization and terminal sterilization step S30, are consistent with Example 1. After the prepared gel is sterilized by moist heat at 121°C for 20 minutes, its G' retention rate and Mw retention rate are detected. This result is significantly superior to Comparative Example 1 (no protection, G' retention rate 42.3%) and Comparative Example 2 (mannitol protection, G' retention rate 74.5%). The results of this embodiment demonstrate that the core inventive concept of this application—the construction of a dual-protection system by combining a solvated shell-building agent (such as ectoine or a trehalose derivative) and a high-temperature free radical scavenger (such as carnosine or ferulic acid)—is not limited to a specific combination of compounds but is a universally applicable technical solution. As long as this synergistic protection mechanism is followed and substances of the appropriate functional class are selected, highly efficient protection of cross-linked sodium hyaluronate gel during high-temperature moist heat sterilization can be achieved.

[0053] The above description is merely a preferred embodiment of this application and is not intended to limit this application. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this application should be included within the protection scope of this application.

Claims

1. A sodium hyaluronate gel, characterized in that, The gel comprises: cross-linked sodium hyaluronate, a solvated shell-building agent, and a high-temperature free radical scavenger; The total weight percentage content of the solvated shell building agent and the high-temperature free radical scavenger is 0.1% to 1.0%; The solvated shell-building agent is selected from at least one of ectoine or amphiphilic trehalose derivatives; The high-temperature free radical scavenger is selected from at least one of carnosine or ferulic acid.

2. The sodium hyaluronate gel according to claim 1, characterized in that, The solvation shell builder is ectoine, and the high-temperature free radical scavenger is carnosine.

3. The sodium hyaluronate gel according to claim 1, characterized in that, The amphiphilic trehalose derivative is selected from trehalose dipalmitate.

4. A sodium hyaluronate gel according to claim 1 or claim 2, characterized in that, The cross-linked sodium hyaluronate has a weight percentage content of 1.5% to 3.0%.

5. A sodium hyaluronate gel according to claim 1 or 2, characterized in that, The cross-linked sodium hyaluronate was obtained by cross-linking with 1,4-butanediol diglycidyl ether as a cross-linking agent.

6. A sodium hyaluronate gel according to claim 1 or 2, characterized in that, The gel also contains lidocaine hydrochloride.

7. A sodium hyaluronate gel according to claim 1 or 2, characterized in that, The solvation shell builder is ectoine, and the high-temperature free radical scavenger is carnosine; and the gel is in Moist heat sterilization Minutes later, energy storage modulus Retention rate ≥ 96%.

8. A method for preparing sodium hyaluronate gel according to any one of claims 1-7, characterized in that, Includes the following steps: S1: Sodium hyaluronate is reacted with a crosslinking agent to obtain a crude crosslinked gel; S2: The coarse cross-linked gel is placed in a buffer solution containing a solvated shell building agent and a high-temperature free radical scavenger for dialysis equilibration to load the solvated shell building agent and the high-temperature free radical scavenger into the gel network; The dialysis equilibrium temperature is between 20°C and 30°C, the time is at least 24 hours, and the dialysate is replaced at least once during this period; S3: After homogenizing the gel obtained in step S2, perform terminal moist heat sterilization.

9. The method according to claim 8, characterized in that, The terminal moist heat sterilization is carried out at a temperature of 121°C.

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