A bioactive glass-based remineralization repair gel for tooth enamel

Abstract

The application relates to the technical field of tooth enamel repair, and discloses a tooth enamel remineralization repair gel based on bioactive glass, which comprises choline chloride, urea, anhydrous disodium hydrogen phosphate, anhydrous sodium citrate powder, 45S5 type bioactive glass, sodium alginate powder and urease freeze-dried powder. In preparation, the powder components are dispersed in anhydrous eutectic solvent synthesized by choline chloride and urea. The application cuts off the precipitation path of calcium ions in the storage period by using the anhydrous matrix, triggers in-situ crosslinking of sodium alginate and calcium ions to form a film after coating, and effectively resists fluid scouring. In the limited space formed by the gel, urea is catalyzed by urease to produce ammonia to promote nucleation, and meanwhile, the micronized citrate root preferentially dissolves and is adsorbed on the calcium phosphate crystal nucleus surface to guide directional crystallization. The application avoids disordered precipitation of calcium and phosphorus ions, and can reconstruct a dense biomimetic crystal column repair layer with excellent mechanical hardness on the demineralized tooth surface.

Description

Technical Field

[0001] This invention relates to the field of enamel repair technology, specifically to a enamel remineralization repair gel based on bioactive glass. Background Technology

[0002] Enamel demineralization is a core early pathological process leading to tooth decay and sensitivity. Remineralization repair of demineralized tooth surfaces through the external introduction of calcium- and phosphorus-containing materials is currently the primary method of clinical intervention and daily care. Bioactive glass, due to its ability to undergo network degradation in physiological environments and continuously release precursor ions such as calcium, phosphorus, and silicon, is widely used in the development of dental restorative products.

[0003] Traditional repair formulations based on bioactive glass typically use aqueous gels or emulsions as the carrier matrix. In this aqueous environment, the bioactive glass powder is highly susceptible to surface hydration during product storage, prematurely releasing trace amounts of free calcium ions. Once these free divalent ions come into contact with the polymeric thickeners commonly added to the formulation system, they trigger uncontrolled chain segment coordination and cross-linking reactions, causing premature solidification or the formation of amorphous clumps within the packaging tube, fundamentally compromising the rheological stability and shelf life of the formulation.

[0004] To avoid early reactions during the aforementioned storage period, existing technologies often employ physical isolation packaging or reduce the concentration of active powder. However, this fails to address the practical challenges faced by the formulation during clinical application. When the restorative agent is applied to the tooth surface, the continuous secretion of saliva in the oral cavity creates a strong fluid erosion effect on the coating. Conventional aqueous systems, lacking an in-situ film-forming mechanism in response to external stimuli, are easily diluted and disintegrated by saliva. The active precursor is largely lost with the fluid before it can be absorbed by the underlying enamel, failing to maintain a sufficient concentration and adhesion time at the lesion interface.

[0005] Furthermore, even if some calcium and phosphate ions are locally deposited on the tooth surface, free ions typically tend to undergo disordered homogeneous precipitation in the complex acid-base buffering system of the oral cavity. Existing formulations lack methods to continuously raise the pH value of the local tooth microenvironment and fail to introduce physicochemical mechanisms to interfere with the nucleation and crystallization direction of calcium phosphate. This results in most mineralized products being stacked on the tooth surface in a loose, amorphous, non-crystalline structure. These non-crystalline deposits contain numerous pores, and their microstructure differs significantly from the highly ordered columnar hydroxyapatite crystals of natural tooth enamel. They cannot provide the mechanical hardness required to resist chewing abrasion and are insufficient to reconstruct a strong, load-bearing restorative layer in the demineralized area. Summary of the Invention

[0006] To address the shortcomings of existing technologies, this invention provides a remineralized enamel repair gel based on bioactive glass, which solves the problems of conventional aqueous repair preparations being prone to cross-linking and curing during storage, having low adhesion and retention rates in the oral flushing environment, and having a loose structure of amorphous mineralized deposits that are difficult to reconstruct into a dense and high-strength enamel repair layer.

[0007] To achieve the above objectives, the first aspect of the present invention provides a dental enamel remineralization repair gel based on bioactive glass, comprising the following components in parts by weight: choline chloride: 28.0–35.0 parts; urea: 22.0–28.0 parts; anhydrous disodium hydrogen phosphate: 3.0–6.0 parts; anhydrous sodium citrate powder: 2.0–4.5 parts; 45S5 type bioactive glass powder: 15.0–25.0 parts; sodium alginate powder: 1.0–2.5 parts; and urease lyophilized powder: 0.1–0.5 parts.

[0008] By employing the above-mentioned technical solution, using a high-viscosity, low-eutectic solvent synthesized from choline chloride and urea as a fluid carrier, the ion dissociation pathway induced by water molecules can be blocked. Under this environment, the early precipitation of calcium ions inside the bioactive glass is restricted, and the sodium alginate molecular chains in the system naturally cannot undergo early coordination cross-linking, thereby ensuring the long-term rheological stability of the gel.

[0009] When this gel is applied to the tooth surface and comes into contact with saliva, the original anhydrous phase disintegrates. The infiltration of ambient moisture into the system directly triggers the swelling and release of the polymeric components. The released sodium alginate segments then combine with divalent calcium ions dissolved from the bioactive glass, forming a network cross-link that rapidly constructs a physical barrier layer at the enamel interface. This gel film blocks the channels through which internal active substances can dissipate to external fluids.

[0010] At this point, urease specifically catalyzes the hydrolysis of the substrate urea. The gaseous ammonia generated by the reaction is confined by the outer gel network and cannot easily escape, but can only remain in the liquid film close to the tooth interface, forcing the pH value of the microenvironment in this area to rise rapidly to the alkaline range. At the same time, anhydrous disodium hydrogen phosphate and bioactive glass simultaneously output calcium and phosphorus sources, and the alkaline environment provides the necessary thermodynamic conditions for the inorganic phase to reach supersaturation and for calcium phosphate to nucleate.

[0011] The free citrate anions in the early nucleation stage interfere with crystal development through steric hindrance. Based on the principle of molecular configuration matching, citrate ions can specifically adsorb onto the crystal faces of the initial calcium phosphate nuclei. This adsorption behavior inhibits the disordered proliferation of nuclei along the a-axis and b-axis, and instead guides the inorganic phase to grow directionally along the c-axis. Ultimately, the precipitated phase develops into a densely packed biomimetic crystal column group, which transforms into a crystalline repair layer with high Vickers hardness mechanical support on the demineralized glaze surface.

[0012] Preferably, the median particle size D50 of anhydrous sodium citrate powder is 0.6–1.9 μm; and the median particle size D50 of sodium alginate powder is 85.0–115.0 μm.

[0013] By employing the above technical solution and utilizing a specific particle size distribution difference, a clear dissolution time difference can be established in the initial stage of phase change hydration. Micron-sized anhydrous sodium citrate, with its larger specific surface area, dissolves preferentially compared to larger sodium alginate particles. Therefore, citrate ions that enter the liquid phase earlier can preemptively chelate with the released primary calcium ions, effectively delaying the rapid increase in local free calcium ion concentration. This spatiotemporal differential dissolution mechanism prevents the formation of unhydrated agglomerates due to encapsulation of internal dry powder, ensuring the macroscopic uniformity of the final gel film and its interfacial adhesion under dynamic fluid scouring conditions.

[0014] Preferably, the median particle size D50 of the 45S5 type bioactive glass powder is 5.0 to 10.0 μm, specifically including silicon dioxide, sodium oxide, calcium oxide and phosphorus pentoxide.

[0015] By employing the above technical solution, the silicate network structure formulated in the specific ratio exhibits a suitable degradation rate in an aqueous environment. Because the particle size is controlled within a set micrometer range, the powder not only maintains uniform suspension in a highly viscous eutectic matrix, but also establishes a stable calcium ion and silicate ion export gradient in the hydrated microenvironment, providing substrate support for subsequent continuous mineralization reactions.

[0016] Preferably, the urease lyophilized powder has an labeled enzyme activity of 1000 U / g to 3000 U / g and a free water content of <1.0 wt% in the freeze-dried state.

[0017] By employing the above technical solution, urease is in a freeze-dried state with low free water content, eliminating the potential interference of residual moisture on the anhydrous fluid medium and the conformational stability of the protein itself. The defined enzyme activity range keeps the rate of ammonia production at a controllable level, ensuring the continuity of alkalinity enhancement in the local microenvironment while preventing gas expansion or even structural rupture inside the gel coating due to excessive instantaneous gas production.

[0018] A second aspect of this invention provides a method for preparing a dental enamel remineralization repair gel based on bioactive glass, comprising the following steps: Anhydrous sodium citrate crystals and sodium alginate powder were pulverized and sieved to obtain the corresponding pre-prepared powders. Choline chloride and urea are added to a closed reaction vessel, heated and the vacuum system is turned on. Under the condition of heat preservation and pressure preservation, the free water is continuously stirred to remove the free water and form a homogeneous high viscosity low eutectic solvent fluid. Release the vacuum in the reactor and introduce refrigerant into the reactor jacket to cool it down, so that the temperature of the fluid inside the reactor decreases and stabilizes at room temperature. While maintaining continuous stirring, add the specified weight parts of anhydrous disodium hydrogen phosphate, anhydrous sodium citrate powder, 45S5 type bioactive glass powder, sodium alginate powder and urease lyophilized powder to the reactor in sequence for preliminary dispersion and premixing. Turn on the high-shear system to perform temperature-controlled high-shear homogenization of the premixed materials; After homogenization, the high-shear system was turned off, and the system was vacuumed and allowed to stand to degas. Then, vacuum filling and sealing were performed in an anhydrous environment to obtain the enamel remineralization repair gel.

[0019] By employing the above technical solution, after the basic fluid is constructed under heating and vacuum conditions, forced heat exchange is immediately introduced to terminate the thermal effect, bringing the entire system back to and stabilizing it within the room temperature range before the addition and homogenization of each powder component are performed. This avoids the risk of thermally induced phase transition crosslinking between inorganic powders and polymers in high-temperature fluids and preserves the catalytic activity of enzymes. The final high-shear combined with vacuum degassing process breaks down the electrostatic agglomeration structure between fine powder particles, establishing a long-term physical anti-settling state for the entire gel system.

[0020] Preferably, the pre-preparation of anhydrous sodium citrate powder includes: weighing anhydrous sodium citrate crystals and placing them in a vacuum drying oven with an absolute pressure of 0.03-0.05 MPa, and drying them at a constant temperature of 105-110°C for 4-6 hours; after removal, feeding them into a fluidized bed jet mill under a dry nitrogen protective atmosphere, and pulverizing them at a pulverizing pressure of 0.6-0.8 MPa and a classifying wheel speed of 4000-5500 rpm, and collecting the powder through a cyclone collector.

[0021] By employing the above technical solution, the medium-temperature combined vacuum negative pressure environment can remove physically adsorbed water adhering to the crystal lattice surface, while the closed dry nitrogen system cuts off the path of external moisture intrusion during the pulverization process. Through high-speed airflow pulling the crystals to undergo self-impact, the particle size of the powder is refined and converges to an extremely narrow distribution domain, providing a phase basis for establishing accurate differential dissolution during subsequent system hydration.

[0022] Preferably, the pre-preparation of sodium alginate powder includes: placing sodium alginate powder in a vacuum drying oven and drying it at a constant temperature of 45-50℃ for 8-10 hours; after removal, dry sieving is performed using a vibrating multi-layer standard sieve.

[0023] By adopting the above technical solution, the gentle vacuum dehydration process removes free water between polymer chain segments while avoiding the temperature range that triggers thermal degradation of the polysaccharide backbone. Subsequent physical dry sieving removes excessively fine powder and oversized irregular particles, leaving a relatively concentrated particle size distribution of coarse powder, ensuring that the initiation threshold of the water-based cross-linking reaction of sodium alginate remains consistent.

[0024] Preferably, after choline chloride and urea are added to the closed reactor, the temperature of the material inside the reactor is controlled to rise to 80-85°C, the absolute pressure of the vacuum system is set to 0.06-0.08 MPa, the stirring speed is 50-80 rpm, and the stirring time is 40-50 min.

[0025] By employing the above technical solution, a constant heat input combined with a depressurization field drives hydrogen bonding between choline chloride and urea, two solid materials, leading to a liquid phase transition. During this phase transition, trace amounts of moisture entrained in the raw materials are simultaneously flash-evaporated. The precisely controlled stirring speed and time ensure uniform heat transfer during the formation of the highly viscous fluid, eliminating any unmelted dead zones that may remain at the bottom of the vessel.

[0026] Preferably, the cooling process involves introducing a refrigerant, specifically: introducing chilled brine into the reactor jacket and turning on the external circulation pump for forced convection, thereby stabilizing the fluid temperature at 20-25°C within 15-25 minutes.

[0027] By adopting the above technical solution, the thermodynamic state of the fluid matrix can be anchored back to the safe operating range of room temperature within a limited time, eliminating the hidden danger of unexpected thermal modification caused by subsequent incorporation of active powder.

[0028] Preferably, the temperature-controlled high-shear homogenization treatment of the premixed material specifically includes: setting the high-shear speed to 3000-3500 rpm, the homogenization time to 20-30 min, and running the cooling system at full load during the homogenization period to control the temperature of the premixed material to be less than 30°C.

[0029] By adopting the above technical solution, the strong mechanical shear force generated by high-speed operation overcomes the extremely high viscosity damping of the matrix fluid itself, forcibly tearing apart the agglomerates between solid particles so that they are fully wetted by the fluid. In order to counteract the huge shear heat generated by the high-frequency friction between the stator and rotor, a full-load cooling cycle is simultaneously applied during homogenization, strictly controlling the system's extreme temperature below 30°C, thus avoiding enzyme inactivation caused by temperature rise and powder sedimentation and separation caused by the dilution of the medium.

[0030] Preferably, the time for vacuuming and standing to remove bubbles is 10 to 15 minutes.

[0031] By adopting the above technical solution, the existence of negative pressure gradient forces the microbubbles that were drawn into the depths of the fluid by the high shear action in the early stage to expand in volume, and then float to the surface and disintegrate.

[0032] This invention provides a dental enamel remineralization repair gel based on bioactive glass. It possesses the following beneficial effects: 1. This invention uses an anhydrous eutectic solvent synthesized from choline chloride and urea as a fluid matrix, combined with sodium alginate powder of a specific particle size and bioactive glass. This can interrupt the aqueous phase pathway of calcium ion precipitation during storage and trigger in-situ cross-linking of polymer segments and primary free calcium ions to form a film after the formulation is coated and comes into contact with saliva. This avoids early cross-linking and curing of the formulation in the packaging and rapid rinsing and loss of the formulation by fluids during oral use. This solves the problems of short storage life and insufficient effective action time in the dynamic oral environment of conventional aqueous repair gels.

[0033] 2. This invention utilizes urease to catalyze the continuous hydrolysis of urea substrate within the locally confined space formed by the cross-linking of the gel network. This allows the generated ammonia gas to be trapped in the liquid phase boundary near the tooth surface, thereby steadily increasing and maintaining the pH value of this microenvironment in a slightly alkaline range. This prevents the mineralized ions released by the bioactive glass from being continuously buffered, diluted, and neutralized by saliva in the open system, thus solving the problem that conventional coating systems are unable to establish and maintain the thermodynamic conditions required for heterogeneous nucleation of calcium phosphate on the damaged tooth surface.

[0034] 3. This invention introduces pre-micronized anhydrous sodium citrate to establish a time-space difference that prioritizes the dissolution of polymer powders. This allows the pre-released free citrate ions to selectively adsorb onto the initial calcium phosphate crystal nuclei, creating steric hindrance and guiding the inorganic phase to grow into densely packed biomimetic crystal pillars. This avoids the spontaneous and disordered homogeneous precipitation of free calcium and phosphate ions at the demineralization interface, thus solving the problem that existing formulations can usually only generate loose and amorphous deposits and cannot reconstruct a crystalline repair layer with solid mechanical hardness support on the demineralized enamel surface. Attached Figure Description

[0035] Figure 1 The graph shows the stability test results of the gel system of the present invention in accelerated aging test, wherein (a) is the graph of apparent viscosity changing with time, and (b) is the graph of free calcium ion concentration changing with time. Figure 2 This is a graph showing the dynamic pH change of the internal microenvironment of the gel system of the present invention under artificial saliva triggering. Figure 3The distribution of test results for the macroscopic hydration film-forming properties and anti-fluid erosion properties of the gel system of the present invention is shown in the figure; wherein, (a) is a bar chart of the mass percentage of hard unhydrated interstitial agglomerates generated after the hydrogel triggers phase change, and (b) is a bar chart of the mass retention rate of the system on the surface of the extracted tooth after 120 minutes of constant artificial saliva erosion. Figure 4 The diagram shows the distribution of macroscopic mechanical remineralization assessment of the gel-treated enamel samples of the present invention. (a) is a graph showing the trend of microhardness values ​​from the initial healthy stage through three cycles of demineralization to remineralization treatment, and (b) is a graph showing the distribution of the relative recovery rate of microhardness for each test object. Detailed Implementation

[0036] The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0037] The main raw materials and reagents used in the following examples and comparative examples have the following sources and specifications. Reagents not specifically mentioned are all commercially available analytical grade or higher grade products.

[0038] Choline chloride, with the molecular formula C5H 14 ClNO, CAS number 67-48-1, has a free water content of less than 0.5 wt%.

[0039] Urea, chemically known as carbodiamine, with the molecular formula CH4N2O and CAS number 57-13-6, is a white crystalline powder with a free water content of less than 0.5 wt% and is of analytical grade.

[0040] The 45S5 type bioactive glass powder is composed of 45wt% silicon dioxide (SiO2), 24.5wt% sodium oxide (Na2O), 24.5wt% calcium oxide (CaO) and 6wt% phosphorus pentoxide (P2O5) by mass percentage, which are melt-quenched and have a median particle size D50 of 5.0 to 10.0 μm.

[0041] Anhydrous disodium hydrogen phosphate is a white, highly hygroscopic powder that decomposes into sodium pyrophosphate at 250°C. It is of analytical grade.

[0042] Sodium alginate powder, chemically known as sodium alginate, CAS number 9005-38-3, is a linear block copolymer composed of β-D-mannuronic acid (M unit) and α-L-guluronic acid (G unit) linked by (1 to 4) bonds, with a weight-average molecular weight range of 1.0 × 10⁻⁶. 5~5.0×10 5 Between Da and G, the molar ratio (M / G ratio) of M unit to G unit is 1.0 to 1.5.

[0043] Anhydrous sodium citrate crystals, CAS number 68-04-2, are white granular crystals that do not contain water of crystallization.

[0044] Urease lyophilized powder is a specific protein enzyme that catalyzes the hydrolysis of urea, obtained by extraction and purification from sword bean. Its CAS number is 9002-13-5, and its enzyme activity is indicated to be 1000U / g~3000U / g. The free water content in the freeze-dried state is less than 1.0wt%.

[0045] Sodium polyaspartate, CAS number 181828-06-8, has a weight-average molecular weight range of 2000 to 5000 Da.

[0046] Preparation Example 1: This preparation example provides a method for preparing anhydrous sodium citrate powder, including the following steps: Anhydrous sodium citrate crystals were weighed and placed in a vacuum drying oven, where they were dried at 110℃ and 0.03 MPa absolute pressure for 6 hours. After removal, they were fed into a fluidized bed jet mill under a nitrogen atmosphere for further pulverization. The pulverizing pressure was set to 0.8 MPa, and the classifier speed to 5500 rpm. After pulverization, the powder was collected using a cyclone collector, ensuring a median particle size (D50) of 0.6 μm. The resulting powder was then vacuum-sealed in aluminum foil bags containing a desiccant for later use.

[0047] Preparation Example 2: This preparation example provides a method for preparing anhydrous sodium citrate powder, including the following steps: Anhydrous sodium citrate crystals were weighed and placed in a vacuum drying oven, where they were dried at 108℃ and 0.04 MPa absolute pressure for 5 hours. After removal, the crystals were fed into a fluidized bed jet mill under a nitrogen atmosphere for further pulverization. The pulverizing pressure was set to 0.7 MPa, and the classifier speed to 4800 rpm. After pulverization, the powder was collected using a cyclone collector, resulting in a median particle size (D50) of 1.2 μm. The obtained powder was then vacuum-sealed in aluminum foil bags containing a desiccant for later use.

[0048] Preparation Example 3: This preparation example provides a method for preparing anhydrous sodium citrate powder, including the following steps: Anhydrous sodium citrate crystals were weighed and placed in a vacuum drying oven, where they were dried at 105℃ and 0.05 MPa absolute pressure for 4 hours. After removal, the crystals were fed into a fluidized bed jet mill under a nitrogen atmosphere for further pulverization. The pulverizing pressure was set to 0.6 MPa, and the classifier speed to 4000 rpm. After pulverization, the powder was collected using a cyclone collector, resulting in a median particle size (D50) of 1.9 μm. The obtained powder was then vacuum-sealed in aluminum foil bags containing a desiccant for later use.

[0049] Preparation Example 4: This preparation example provides a method for preparing sodium alginate powder, including the following steps: Sodium alginate powder was weighed and spread evenly in a shallow dish, then placed in a vacuum drying oven and dried at 45℃ and 0.05MPa absolute pressure for 10 hours to remove free water. After removal, it was dry-sieved using a vibrating multi-layer standard sieve, and the powder fraction retained between 75μm and 95μm pore sizes was collected. The median particle size (D50) was measured to be 85.0μm using a laser particle size analyzer. The obtained powder was then vacuum-sealed in aluminum foil bags for later use.

[0050] Preparation Example 5: This preparation example provides a method for preparing sodium alginate powder, including the following steps: Sodium alginate powder was weighed and spread evenly in a shallow dish, then placed in a vacuum drying oven and dried at 48℃ and 0.05MPa absolute pressure for 9 hours to remove free water. After removal, it was dry-sieved using a vibrating multi-layer standard sieve, and the powder fraction retained between 90μm and 110μm pore sizes was collected. Laser particle size analyzer analysis showed a median particle size (D50) of 100.0μm. The obtained powder was then vacuum-sealed in aluminum foil bags for later use.

[0051] Preparation Example 6: This preparation example provides a method for preparing sodium alginate powder, including the following steps: Sodium alginate powder was weighed and spread evenly in a shallow dish, then placed in a vacuum drying oven and dried at 50℃ and 0.05MPa absolute pressure for 8 hours to remove free water. After removal, it was dry-sieved using a vibrating multi-layer standard sieve, and the powder fraction retained between 105μm and 125μm pore sizes was collected. The median particle size (D50) was measured to be 115.0μm using a laser particle size analyzer. The obtained powder was then vacuum-sealed in aluminum foil bags for later use.

[0052] Example 1: This embodiment provides a method for preparing a dental enamel remineralization repair gel based on bioactive glass, including the following steps: Step 1: Weigh 28.0 parts of choline chloride and 22.0 parts of urea and add them to a sealed reactor equipped with a jacketed heat exchange system, an external circulation pump, a wall-scraping agitator, and a bottom high-shear dispersion head. Heat the material in the reactor to 80°C, turn on the vacuum system to reduce the absolute pressure to 0.08 MPa, and stir continuously at 50 rpm for 40 minutes under the heat and pressure holding conditions. Use the vacuum field to remove free water and form a homogeneous high-viscosity eutectic solvent fluid.

[0053] Step 2: Release the vacuum, introduce chilled brine into the reactor jacket and turn on the external circulation pump to force convection, forcibly reducing the temperature of the fluid in the reactor to 25°C within 25 minutes.

[0054] Step 3: After confirming that the fluid temperature is stable at 25°C and under continuous stirring, add 3.0 parts of anhydrous disodium hydrogen phosphate, 2.0 parts of anhydrous sodium citrate powder prepared in Preparation Example 3, 15.0 parts of 45S5 type bioactive glass powder with a median particle size D50 of 10.0 μm, 1.0 part of sodium alginate powder prepared in Preparation Example 4, and 0.1 parts of urease lyophilized powder to the reactor for preliminary dispersion and premixing.

[0055] Step 4: Turn on the high-shear dispersion head, set the rotation speed to 3000 rpm, and perform temperature-controlled high-shear homogenization for 20 minutes. During homogenization, run the cooling system at full load, monitor and ensure that the highest local temperature of the fluid in the high-shear core region does not exceed 30°C.

[0056] Step 5: After homogenization, turn off the high shear system, turn on the vacuum system to an absolute pressure of 0.05 MPa, let it stand for 10 minutes to degas, and then vacuum fill and seal the gel in an anhydrous environment with an absolute air humidity of less than 20%.

[0057] Example 2: This embodiment provides a method for preparing a dental enamel remineralization repair gel based on bioactive glass, including the following steps: Step 1: Weigh 31.5 parts of choline chloride and 25.0 parts of urea and add them to a sealed reactor equipped with a jacketed heat exchange system, an external circulation pump, a wall-scraping agitator, and a bottom high-shear dispersion head. Heat the material in the reactor to 82°C, turn on the vacuum system to reduce the absolute pressure to 0.07 MPa, and stir continuously at 65 rpm for 45 minutes under the heat and pressure holding conditions. Use the vacuum field to remove free water and form a homogeneous high-viscosity eutectic solvent fluid.

[0058] Step 2: Release the vacuum, introduce chilled brine into the reactor jacket and turn on the external circulation pump to force convection, forcibly reducing the temperature of the fluid in the reactor and stabilizing it at 22°C within 20 minutes.

[0059] Step 3: After confirming that the fluid temperature is stable at 22℃ and under continuous stirring, add 4.5 parts of anhydrous disodium hydrogen phosphate, 3.2 parts of anhydrous sodium citrate powder prepared in Preparation Example 2, 20.0 parts of 45S5 type bioactive glass powder with a median particle size D50 of 7.5μm, 1.8 parts of sodium alginate powder prepared in Preparation Example 5 and 0.3 parts of urease lyophilized powder to the reactor for preliminary dispersion and premixing.

[0060] Step 4: Turn on the high-shear dispersion head, set the rotation speed to 3200 rpm, and perform temperature-controlled high-shear homogenization for 25 minutes. During homogenization, run the cooling system at full load, monitor and ensure that the highest local temperature of the fluid in the high-shear core region does not exceed 30°C.

[0061] Step 5: After homogenization, turn off the high shear system, turn on the vacuum system to an absolute pressure of 0.05 MPa, let it stand for 12 minutes to degas, and then vacuum fill and seal the gel in an anhydrous environment with an absolute air humidity of less than 20%.

[0062] Example 3: This embodiment provides a method for preparing a dental enamel remineralization repair gel based on bioactive glass, including the following steps: Step 1: Weigh 35.0 parts of choline chloride and 28.0 parts of urea and add them to a sealed reactor equipped with a jacketed heat exchange system, an external circulation pump, a wall-scraping agitator, and a bottom high-shear dispersion head. Heat the material in the reactor to 85°C, turn on the vacuum system to reduce the absolute pressure to 0.06 MPa, and stir continuously at 80 rpm for 50 minutes under the heat and pressure holding conditions. Use the vacuum field to remove free water and form a homogeneous high-viscosity eutectic solvent fluid.

[0063] Step 2: Release the vacuum, introduce chilled brine into the reactor jacket and turn on the external circulation pump to force convection, forcibly reducing the temperature of the fluid in the reactor to 20°C within 15 minutes.

[0064] Step 3: After confirming that the fluid temperature is stable at 20°C and under continuous stirring, add 6.0 parts of anhydrous disodium hydrogen phosphate, 4.5 parts of anhydrous sodium citrate powder prepared in Preparation Example 1, 25.0 parts of 45S5 type bioactive glass powder with a median particle size D50 of 5.0 μm, 2.5 parts of sodium alginate powder prepared in Preparation Example 6, and 0.5 parts of urease lyophilized powder to the reactor for preliminary dispersion and premixing.

[0065] Step 4: Turn on the high-shear dispersion head, set the rotation speed to 3500 rpm, and perform temperature-controlled high-shear homogenization for 30 minutes. During homogenization, run the cooling system at full load, monitor and ensure that the highest local temperature of the fluid in the high-shear core region does not exceed 30°C.

[0066] Step 5: After homogenization, turn off the high shear system, turn on the vacuum system to an absolute pressure of 0.05 MPa, let it stand for 15 minutes to degas, and then vacuum fill and seal the gel in an anhydrous environment with an absolute air humidity of less than 20%.

[0067] Example 4: This embodiment provides a method for preparing a dental enamel remineralization repair gel based on bioactive glass, including the following steps: Step 1: Weigh 28.0 parts of choline chloride and 22.0 parts of urea and add them to a sealed reactor equipped with a jacketed heat exchange system, an external circulation pump, a wall-scraping agitator, and a bottom high-shear dispersion head. Heat the material in the reactor to 82°C, turn on the vacuum system to reduce the absolute pressure to 0.07 MPa, and stir continuously at 65 rpm for 45 minutes under the heat and pressure holding conditions. Use the vacuum field to remove free water and form a homogeneous high-viscosity eutectic solvent fluid.

[0068] Step 2: Release the vacuum, introduce chilled brine into the reactor jacket and turn on the external circulation pump to force convection, forcibly reducing the temperature of the fluid in the reactor and stabilizing it at 22°C within 20 minutes.

[0069] Step 3: After confirming that the fluid temperature is stable at 22°C and under continuous stirring, add 6.0 parts of anhydrous disodium hydrogen phosphate, 4.5 parts of anhydrous sodium citrate powder prepared in Preparation Example 1, 25.0 parts of 45S5 type bioactive glass powder with a median particle size D50 of 5.0 μm, 2.5 parts of sodium alginate powder prepared in Preparation Example 6, and 0.5 parts of urease lyophilized powder to the reactor for preliminary dispersion and premixing.

[0070] Step 4: Turn on the high-shear dispersion head, set the rotation speed to 3200 rpm, and perform temperature-controlled high-shear homogenization for 25 minutes. During homogenization, run the cooling system at full load, monitor and ensure that the highest local temperature of the fluid in the high-shear core region does not exceed 30°C.

[0071] Step 5: After homogenization, turn off the high shear system, turn on the vacuum system to an absolute pressure of 0.05 MPa, let it stand for 12 minutes to degas, and then vacuum fill and seal the gel in an anhydrous environment with an absolute air humidity of less than 20%.

[0072] Comparative Example 1: Compared with Example 2, the difference is that the anhydrous sodium citrate powder obtained in Preparation Example 2 was replaced with an equal amount of commercially available anhydrous sodium citrate powder that was not pulverized, and the sodium alginate powder obtained in Preparation Example 5 was replaced with an equal amount of commercially available commercially available sodium alginate fine powder that was not sieved. All other aspects are the same.

[0073] Comparative Example 2: Compared with Example 2, the difference is that the anhydrous sodium citrate powder obtained in Example 2 was replaced with an equal mass of conventional water-soluble macromolecular scale inhibitor polyaspartic acid powder, otherwise the same.

[0074] Comparative Example 3: The difference between Example 2 and Example 3 is that urease lyophilized powder was not added to the formulation; all other aspects are the same.

[0075] Comparative Example 4: The difference between Example 2 and Example 3 is that the sodium alginate powder prepared in Example 5 was not added to the formulation; otherwise, they are the same.

[0076] Comparative Example 5: Compared with Example 2, the difference is that the fluid matrix was changed, and choline chloride and urea were replaced with a mixture of deionized water and glycerol of equal total mass (mass ratio of 1:1). The vacuum dehydration and heating operation was cancelled, and each powder component was directly added to the water / glycerol mixture at room temperature for stirring and homogenization. All other aspects were the same.

[0077] Test Example 1: 1. Test objective: To verify the actual effectiveness of the precipitation of free calcium ions and the early cross-linking reaction of macromolecules in the frozen system when the eutectic solvent forms an anhydrous fluid matrix.

[0078] 2. Sample setup: Repair gel samples prepared and encapsulated according to Examples 1, 2, 3, 4 and Comparative Example 5 were placed in a constant temperature accelerated aging test chamber at a set temperature of 40°C and stored in the dark.

[0079] 3. Testing steps: 3.1 Samples were taken on days 0, 15, 30, and 60 of storage, and the macroscopic apparent viscosity of each sample was tested using a rotational rheometer. The test conditions were set as follows: temperature 25℃, constant shear rate 10s. -1 Rheological parameters were recorded to determine whether sodium alginate had prematurely cross-linked and solidified inside the matrix.

[0080] 3.2 At the same sampling time point, weigh each gel sample, dissolve it in anhydrous methanol, and centrifuge to extract it. Use a calibrated calcium ion selective electrode to determine the free Ca in the supernatant. 2+ Concentration reflects the ion release from the bioactive glass in the matrix. The test results are shown in Table 1: Table 1: Changes in viscosity and free calcium ion concentration in Examples 1-4 and Comparative Example 5 under accelerated aging conditions According to Table 1 and Figure 1The data shows that Comparative Example 5, using an aqueous matrix, exhibited significant system instability from the initial preparation stage. Because the aqueous medium provided a direct channel for ion diffusion, free calcium ions rapidly precipitated from the 45S5 bioactive glass, reaching a concentration as high as 45.3 ppm on day 0. Subsequently, divalent calcium ions in the system underwent a cross-linking reaction with the sodium alginate molecular chains, causing the apparent viscosity of Comparative Example 5 to rise to 15840 mPa·s on day 15, approximately 4.8 times its initial value of 3245 mPa·s. The corresponding free calcium concentration decreased to 12.4 ppm due to cross-linking and precipitation consumption. By day 30, the sample had completely cross-linked and solidified, losing its fluidity.

[0081] In contrast, Examples 1 to 4, which used choline chloride-urea eutectic solvent as the anhydrous fluid matrix, maintained good structural stability during the 60-day accelerated aging test. Throughout the test period of these four examples, the concentration of free calcium ions within the system remained at a low level of 0.5 ppm to 1.5 ppm. Simultaneously, the macroscopic viscosity parameters did not undergo abrupt changes; for example, the apparent viscosity of Example 2 only slowly changed from an initial 5103 mPa·s to 5144 mPa·s on day 60. These test data indicate that the anhydrous eutectic matrix can effectively inhibit the premature dissociation and precipitation of free calcium ions, avoiding the swelling and early cross-linking of sodium alginate, thereby ensuring the compatibility stability of each active component during storage and transportation.

[0082] Test Example 2: 1. Test objective: To verify whether the gel system can form a physical barrier through film formation after contact with the aqueous phase, and whether it can increase the pH value of the microenvironment in a locally confined space by using enzymatic reactions.

[0083] 2. Sample setup and testing procedures: 2.1. A rough alumina ceramic sheet is horizontally fixed at the bottom of a constant temperature test tank as a simulated tooth substrate. Artificial saliva solution, pre-adjusted to pH 6.8 and constant temperature 37°C, is injected into the tank so that the liquid level just submerges the surface of the ceramic sheet.

[0084] 2.2 Take quantitative amounts of gel samples from Examples 1, 2, 3, 4, and Comparative Examples 3 and 4, respectively, and spread them evenly on the surface of ceramic sheets immersed in artificial saliva. Control the coating thickness to be approximately 1.5 mm to trigger the hydration phase transition of each system.

[0085] 2.3. At the moment the sample is applied, a micro needle-type pH electrode probe with an outer diameter of 0.5 mm is inserted into the gel coating using a micro-operation stage. The sensing area of ​​the probe is positioned at a distance of about 0.2 mm from the surface of the ceramic sheet, which is used to monitor the local microenvironment pH value of the deep gel layer close to the substrate interface in real time.

[0086] 2.4. Taking the probe insertion time as minute 0, continuously monitor and record the pH values ​​of the system at minutes 1, 5, 10, 15, 20, and 30. Each sample group was tested three times in parallel with a new substrate to obtain the average data. The test results are shown in Table 2. Table 2: Changes in pH value of the internal microenvironment of Examples 1-4 and Comparative Examples 3 and 4 under artificial saliva triggering According to Table 2 and Figure 2 The data shows that after contact with artificial saliva, the pH value of the microenvironment at the bottom interface of Examples 1 to 4 all showed a significant increasing trend. Taking Example 2 as an example, the pH value measured by the bottom probe increased from 7.08 at the 1st minute to 9.31 at the 15th minute, and stabilized in the slightly alkaline range above 9.4 in the latter part of the test cycle. As a control, Comparative Example 3, which did not add urease, lacked the catalytic conditions for urea hydrolysis to produce ammonia, and its internal pH value only slowly increased to 7.55 within 30 minutes. The small change in this range was mainly caused by the basal hydration release of alkali metal oxides in the bioactive glass.

[0087] Comparative Example 4, lacking sodium alginate powder, could not form a continuous hydrogel film through ionic cross-linking in saliva, resulting in a lack of physical sealing at the external interface. The pH of this sample peaked at 7.85 at 10 minutes and then gradually decreased over time, returning to 7.45 by 30 minutes. This indicates that the ammonia generated within the system, unrestricted by space, was flushed away and diffused by the externally flowing artificial saliva, and neutralized by the saliva's buffering system.

[0088] The data comparison above shows that the cross-linking film formation process of sodium alginate and the internal urease catalytic reaction have a clear synergistic effect. The rapid formation of the surface gel layer hinders the outward diffusion of the internal solute, allowing the bottom interface to effectively trap the ammonia gas generated by the hydrolysis reaction, thereby stabilizing the local pH value within the thermodynamic range required to induce calcium phosphate mineralization and crystallization.

[0089] Test Example 3: 1. Test objective: To verify the influence of particle size differences within the system on the macroscopic uniformity of hydration film formation, and the adhesion stability of the cured gel film in a simulated body fluid flow environment.

[0090] 2. Sample setup and testing procedures: 2.1 Evaluation of Film Uniformity: 3.0 g of gel samples from Examples 1, 2, 3, and 4, and Comparative Examples 1 and 4 were weighed and directly squeezed into beakers containing 50 mL of artificial saliva at a constant temperature of 37°C. The samples were allowed to stand for hydration for 15 minutes. The underwater solidified material was removed and transferred to a standard sieve with a pore size of 0.5 mm. The sieve was then lightly wet-sieved under a low-pressure deionized water flow to wash away the uniformly hydrated soft gel, collecting the hard, unhydrated clumps remaining on the sieve. These clumps were placed in a vacuum drying oven at 60°C and dried to constant weight. The percentage of these clumps relative to the total initial solid phase mass of the gel was weighed and calculated.

[0091] 2.2 Evaluation of Erosion Resistance: A smooth-surfaced extracted bovine permanent incisor block was taken, polished with 800-grit silicon carbide sandpaper, ultrasonically cleaned with deionized water for 10 minutes, and then dried. The initial mass of the substrate was measured. 0.5g of the gel sample was evenly coated onto the test surface of the tooth block, which was then fixed in a self-made test flow channel at a 45-degree angle. Artificial saliva at 37°C was drawn using a constant-flow peristaltic pump and continuously dripped at a set flow rate of 1.5mL / min to irrigate the tooth surface coating for 120 minutes. After the test, the tooth block was removed, surface free water was carefully absorbed with filter paper, and the final weight was measured. The mass retention rate of the gel coating after fluid erosion was calculated. Each sample was tested in parallel five times, and the arithmetic mean was taken. The test results are shown in Table 3. Table 3: Film-forming agglomeration rate and erosion resistance retention rate of Examples 1-4 and Comparative Examples 1 and 4 According to Table 3 and Figure 3 The data show that Examples 1 to 4 exhibited high homogeneous film-forming properties after hydration triggered by artificial saliva, with the mass percentage of unhydrated clumps controlled at an extremely low level of 2.05% to 3.82%. After 120 minutes of continuous fluid shear scouring, the gel mass retention rate of the above experimental groups remained stable at over 87.5%, such as 93.1% in Example 2. The test results indicate that this specific formulation system can form a structurally continuous three-dimensional hydrogel network and maintain adhesion on the simulated tooth substrate surface.

[0092] In contrast, Comparative Example 1, which did not employ a specific particle size distribution, generated a high internal unhydrated agglomerate content of 47.63% after contact with the aqueous phase, and its mass retention rate after rinsing dropped sharply to 43.2%. This phenomenon can be attributed to the fact that the dissolution kinetics of the solid components within the system did not exhibit a significant difference. The free calcium ions initially released by the bioactive glass directly cross-linked with the surface of the sodium alginate particles, which had not yet fully absorbed water and expanded, forming a dense calcium-bound shell. This shell physically blocked the mass transfer and penetration of external moisture into the particle interior, causing a large proportion of the polymer powder to be confined within the particle core and unable to participate in overall film formation. This macroscopic structural defect weakened the effective contact area and adhesion strength between the gel layer and the tooth interface, making it highly susceptible to interfacial delamination under fluid shear.

[0093] Comparative Example 4, due to the exclusion of the film-forming matrix sodium alginate in its formulation, failed to construct a cross-linked network microstructure in the aqueous phase. The 0.85% residual solid phase collected during the test was actually inorganic glass residue, with a scouring retention rate of only 8.4%, indicating that the dispersed active powder would be rapidly diluted and carried away by the surrounding liquid flow in an open fluid environment. The comparative analysis of the above test data confirms that the introduction of the particle size difference design between micronized sodium citrate and powdered sodium alginate successfully achieved differential dissolution in the early stage of phase transition and pre-chelation of free calcium ions, thereby avoiding the problem of premature cross-linking of the polymer powder surface. This is the core physicochemical mechanism for constructing a uniform and stable coating in situ in a dynamic fluid environment.

[0094] Test Example 4: 1. Test objective: To use surface microhardness as a macroscopic mechanical index to indirectly demonstrate the compactness of the microstructure of the internal crystalline phase of the system, so as to verify the actual limiting and intervention effect of the crystal morphology guidance mechanism on the crystal growth direction of mineralized sediments.

[0095] 2. Sample Setup: Fresh, intact, and caries-free extracted bovine permanent incisors were selected. Enamel blocks measuring 5mm × 5mm × 3mm were obtained by cutting with a slow-speed diamond saw. The enamel was then polished step-by-step using wet sandpaper until a mirror-like finish was achieved. Examples 1-4 and Comparative Examples 1-5 were selected as the experimental subjects for this test, with six tooth blocks allocated to each sample group for parallel testing.

[0096] 3. Testing steps: 3.1. Using a micro Vickers hardness tester, five different areas on the enamel surface of the tooth block were selected to test the initial microhardness. The applied load was set to 0.98 N, and the holding time was 15 seconds. The average initial hardness (HV) of each group of tooth blocks was recorded. initial ).

[0097] 3.2. Immerse all tooth blocks in lactate demineralization buffer solution with a pH of 4.2 and incubate at 37°C for 72 hours to construct a standard artificial early enamel caries layer. Remove the tooth blocks, clean them ultrasonically, and dry them. Test the surface hardness again using the same parameters and record the average hardness after demineralization (HV). demin ).

[0098] 3.3. 0.2 g of the corresponding test gel sample was uniformly coated onto the surface of the demineralized tooth block and placed in a constant-flow artificial saliva circulation device at 37°C for 14 days of remineralization treatment. During the treatment, the original coating was removed and an equal amount of fresh gel was recoated every 24 hours to simulate daily periodic application conditions.

[0099] 3.4 After the 14-day treatment cycle, the tooth block was ultrasonically washed in deionized water containing sodium hypochlorite for 15 minutes to thoroughly remove the surface-adhered gel matrix and loose inorganic deposits. After drying, the final hardness (HV) of the remineralized interface was measured. remin ), and according to the formula SMHR%=[(HV remin -HV demin ) / (HV initial -HV demin The surface microhardness recovery percentage is calculated as []×100%. The test results are shown in Table 4. Table 4: Changes and recovery rates of enamel microhardness under the treatment of Examples 1-4 and Comparative Examples 1-5 According to Table 4 and Figure 4 Data shows that after 14 days of remineralization treatment, the surface hardness of demineralized enamel in Examples 1 to 4 was significantly improved, with surface microhardness recovery rates (SMHR) ranging from 77.8% to 84.9%. Taking Example 2 as an example, the microhardness after treatment reached 316.5 HV, which is close to its initial healthy state of 341.6 HV. This indicates that free citrate ions in the gel system can selectively adsorb onto the surface of the initial calcium phosphate crystal nuclei based on lattice matching characteristics. By introducing steric hindrance, this mechanism effectively inhibits the isotropic growth of crystals along the a-axis and b-axis, guides the inorganic phase to develop along the c-axis, and ultimately generates a densely packed crystalline layer with high mechanical load-bearing capacity in situ on the tooth surface.

[0100] In contrast, Comparative Example 2 used macromolecular polyaspartic acid instead of sodium citrate. Although the long-chain scale inhibitor retained its chelating ability for initial calcium ion binding, it lacked targeted recognition and adsorption of specific crystal faces of hydroxyapatite. In this state, the system mainly underwent disordered nucleation, and the precipitated amorphous and loose calcium phosphate deposits could not withstand the indentation load of the hardness tester and were easily detached during the ultrasonic elution process, resulting in a hardness recovery rate of only 21.4% for this group.

[0101] Furthermore, in Comparative Example 3, due to the absence of urease, the system could not achieve alkaline transitions in the local microenvironment. Insufficient thermodynamic driving force resulted in a significant reduction in effective deposition, with a hardness recovery rate of only 18.8%. The final hardness recovery rates of Comparative Examples 4 and 5 were as low as 7.3% and 3.3%, respectively, essentially at the baseline level after acid etching and demineralization. These two extreme cases demonstrate that the loss of spatial physical containment and premature solidification caused by early failure of the dielectric system directly interrupt the in-situ reaction pathways of multiple components at the interface. The horizontal comparison of the above data sets confirms a clear synergistic dependence between the free ion confinement, microreactor pH regulation, and specific crystal facet constraint mechanisms within the system, collectively determining the microstructural density and macroscopic mechanical properties of the mineralized layer.

[0102] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A dental enamel remineralization repair gel based on bioactive glass, characterized in that, Includes the following components by weight: Choline chloride: 28.0–35.0 parts; Urea: 22.0–28.0 parts; Anhydrous disodium hydrogen phosphate: 3.0–6.0 parts; Anhydrous sodium citrate powder: 2.0–4.5 parts; 45S5 type bioactive glass powder: 15.0-25.0 parts; Sodium alginate powder: 1.0–2.5 parts; Urease lyophilized powder: 0.1-0.5 parts.

2. The enamel remineralization repair gel based on bioactive glass according to claim 1, characterized in that, The median particle size D50 of the anhydrous sodium citrate powder is 0.6–1.9 μm; the median particle size D50 of the sodium alginate powder is 85.0–115.0 μm.

3. The enamel remineralization repair gel based on bioactive glass according to claim 1, characterized in that, The median particle size D50 of the 45S5 type bioactive glass powder is 5.0 to 10.0 μm, and specifically includes: silicon dioxide, sodium oxide, calcium oxide and phosphorus pentoxide; The urease lyophilized powder has an indicated enzyme activity of 1000 U / g to 3000 U / g, and a free water content of <1.0 wt% in the freeze-dried state.

4. A method for preparing a bioactive glass-based enamel remineralization repair gel as described in any one of claims 1-3, characterized in that, Includes the following steps: Anhydrous sodium citrate crystals and sodium alginate powder were pulverized and sieved to obtain the corresponding pre-prepared powders. Choline chloride and urea are added to a closed reaction vessel, heated and the vacuum system is turned on. Under the condition of heat preservation and pressure preservation, the free water is continuously stirred to remove the free water and form a homogeneous high viscosity low eutectic solvent fluid. Release the vacuum in the reactor and introduce refrigerant into the reactor jacket to cool it down, so that the temperature of the fluid inside the reactor decreases and stabilizes at room temperature. While maintaining continuous stirring, add the specified weight parts of anhydrous disodium hydrogen phosphate, anhydrous sodium citrate powder, 45S5 type bioactive glass powder, sodium alginate powder and urease lyophilized powder to the reactor in sequence for preliminary dispersion and premixing. Turn on the high-shear system to perform temperature-controlled high-shear homogenization of the premixed materials; After homogenization, the high-shear system was turned off, and the system was vacuumed and allowed to stand to degas. Then, vacuum filling and sealing were performed in an anhydrous environment to obtain the enamel remineralization repair gel.

5. The preparation method according to claim 4, characterized in that, The pre-preparation of the anhydrous sodium citrate powder includes: Anhydrous sodium citrate crystals were weighed and placed in a vacuum drying oven with an absolute pressure of 0.03–0.05 MPa, and dried at a constant temperature of 105–110 °C for 4–6 hours. After removal, the crystals were fed into a fluidized bed jet mill under a nitrogen protective atmosphere and pulverized at a pulverizing pressure of 0.6–0.8 MPa and a classifying wheel speed of 4000–5500 rpm. The powder was collected by a cyclone collector.

6. The preparation method according to claim 4, characterized in that, The pre-preparation of the sodium alginate powder includes: Sodium alginate powder was placed in a vacuum drying oven and dried at a constant temperature of 45–50°C for 8–10 hours. After removal, it was dry-sieved using a vibrating multi-layer standard sieve.

7. The preparation method according to claim 4, characterized in that, After choline chloride and urea are added to the sealed reactor, the temperature of the material inside the reactor is controlled to rise to 80-85°C, the absolute pressure of the vacuum system is set to 0.06-0.08 MPa, the stirring speed is 50-80 rpm, and the stirring time is 40-50 min.

8. The preparation method according to claim 4, characterized in that, The cooling process by introducing refrigerant specifically includes: Pass chilled brine into the jacket of the reactor and turn on the external circulation pump to force convection, and stabilize the fluid temperature at 20-25℃ within 15-25 minutes.

9. The preparation method according to claim 4, characterized in that, The temperature-controlled high-shear homogenization treatment of the premixed material specifically includes: setting the high-shear speed to 3000-3500 rpm, the homogenization time to 20-30 min, and running the cooling system at full load during homogenization to control the temperature of the premixed material to <30℃.

10. The preparation method according to claim 4, characterized in that, The vacuuming and static degassing time is 10-15 minutes.

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