Preparation method and application of medical sterile gel coupling agent

Abstract

The application discloses a preparation method and application of a medical sterile gel coupling agent and belongs to the technical field of gel coupling agents for medical examination. First, the in-situ neutralization of acrylic acid is carried out by using the chitosan quaternary ammonium salt in the formula to generate a hydrophilic monomer pre-composite; then the pre-emulsion of the acrylic ester monomer is mixed, and the main network is constructed by initiating copolymerization under an inert atmosphere; subsequently, the tannic acid slurry is introduced in the polymerization later period, and physical crosslinking is realized through the polyphenol structure, so that the medical sterile gel coupling agent is finally prepared. The preparation method and application of the medical sterile gel coupling agent are adopted, through the endogenous neutralization-synchronous complex integrated process, the powerful antibacterial function and the tissue repair function are deeply integrated in the stable gel network, the process makes the key active ingredients produce structure-function synergistic effect, forms an indivisible precision system, and finally the product realizes active antibacterial protection while maintaining excellent imaging performance, and the biocompatibility is excellent.

Description

Technical Field

[0001] This invention relates to the field of gel coupling agents for medical examinations, and in particular to a method for preparing and applying a sterile medical gel coupling agent. Background Technology

[0002] Medical examination gels and ultrasound coupling agents are indispensable media in medical examinations, especially in ultrasound diagnosis and treatment procedures. Besides their lubricating function in medical examinations, their core role in ultrasound examinations is to fill the space between the probe and the skin, eliminating air interference and achieving efficient sound wave transmission, thereby obtaining clear and accurate ultrasound images. Traditional medical ultrasound coupling agents mainly consist of water-soluble polymers (such as carbomer and polyacrylic acid resin), humectants, and water. Their research and development has consistently focused on optimizing acoustic properties (such as sound velocity and sound attenuation), viscosity, stability, and biocompatibility to meet industry standards such as YY / T 0299.

[0003] With the upgrading of clinical needs, especially in scenarios such as interventional ultrasound (e.g., puncture biopsy, drainage), intraoperative ultrasound, and examination of patients with impaired skin barriers (e.g., burns, ulcers), as well as the examination of pathological fistulas (e.g., anal fistulas) in minimally invasive treatments, the function of conventional gel coupling agents as merely acoustic windows is no longer sufficient. These procedures carry a high risk of microbial infection; therefore, developing coupling agents that combine excellent acoustic performance with active antibacterial function has become an important research direction.

[0004] In existing technologies, attempts to endow coupling agents with antibacterial functions mainly fall into two categories:

[0005] Adding antibacterial agents: Small molecule antibacterial agents (such as triclosan and chlorhexidine) or natural antibacterial components are directly incorporated into the prepared gel matrix. Although this method is simple, it has obvious drawbacks: the antibacterial components have weak binding force with the gel network and are prone to migration and precipitation during storage or use, resulting in short antibacterial duration and unstable performance; at the same time, simple physical mixing may destroy the uniformity of the gel and affect the acoustic performance.

[0006] Blending modification: This involves physically blending antibacterial polymers with synthetic polymer solutions. However, due to their poor compatibility, phase separation easily occurs, forming a heterogeneous system, which also affects the product's stability and acoustic uniformity. Furthermore, most natural antibacterial components are sensitive to heat and oxygen, and are easily deactivated during traditional preparation or high-temperature, high-pressure sterilization processes. Summary of the Invention

[0007] The purpose of this invention is to provide a method for preparing and applying a medical sterile gel coupling agent. Through an endogenous neutralization-synchronous compounding integrated process, the potent antibacterial and tissue repair functions are deeply integrated into a stable gel network. This process enables key active ingredients to produce a structure-function synergy effect, forming an inseparable precision system. The final product achieves active antibacterial protection while maintaining excellent imaging performance, and has excellent biocompatibility.

[0008] To achieve the above objectives, the present invention provides a method for preparing a medical sterile gel coupling agent. The medical sterile gel coupling agent, by mass fraction, comprises the following raw materials: 6%-8% acrylic acid, 50%-70% ethyl acrylate, 20%-30% butyl acrylate, 1%-3% AEO-15, 1%-2% sodium dodecyl sulfonate, 3%-5% persulfate, 5%-10% tannic acid, and 2%-8% chitosan quaternary ammonium salt, with the remainder made up by deionized water. The method includes the following steps:

[0009] S1. Pre-emulsification: Dissolve AEO-15 and sodium dodecyl sulfonate in deionized water and stir, then add ethyl acrylate and butyl acrylate and stir to obtain a pre-emulsion.

[0010] S2. Prepare a chitosan quaternary ammonium salt aqueous solution by adding acrylic acid to the chitosan quaternary ammonium salt aqueous solution and stirring to obtain a hydrophilic monomer precomplex.

[0011] S3. Add the pre-emulsion obtained in S1 and the hydrophilic monomer pre-complex obtained in S2 into the reactor, and add persulfate solution dropwise to react. After the reaction, add tannic acid slurry and stir.

[0012] After the stirring reaction in S4 and S3 is completed, the mixture is cooled and sterilized to obtain a sterile medical gel coupling agent.

[0013] Furthermore, the persulfate is one of ammonium persulfate, potassium persulfate, and sodium persulfate, and the chitosan quaternary ammonium salt has a degree of substitution ≥90% and an average molecular weight of 200,000-500,000 Da.

[0014] Preferably, in S1, the stirring speed when dissolving AEO-15 and sodium dodecyl sulfonate in deionized water is 200-400 rpm, and the stirring is continued until completely dissolved. After adding ethyl acrylate and butyl acrylate, the stirring speed is 2500-3500 rpm, and the stirring time is 10-15 min.

[0015] Preferably, in S2, acrylic acid is slowly added dropwise to the chitosan quaternary ammonium salt aqueous solution through a constant pressure dropping funnel or metering pump under cooling conditions of 500-700 rpm and ice water bath. During the dropwise addition, the temperature of the reaction system is maintained between 10-20℃, the total dropwise addition time is controlled within 20-30 min, and the dropwise addition rate is 2-3 mL / min.

[0016] Before preparing the chitosan quaternary ammonium salt aqueous solution, the chitosan quaternary ammonium salt is dried at a temperature of 55-65℃ for 4-4.5 hours. The vacuum degree during drying is ≤-0.095MPa, and the water content of the dried chitosan quaternary ammonium salt is ≤2.0%.

[0017] Preferably, the specific operation of S3 is as follows:

[0018] S31. Deoxygenate the pre-emulsion to obtain a deoxygenated pre-emulsion;

[0019] S32. Mix the deoxygenated pre-emulsion obtained in S31 and the hydrophilic monomer pre-complex obtained in S2, heat and stir to obtain mixed system A;

[0020] S33. Add persulfate solution dropwise to mixture A in S32. After the addition is complete, mixture B is obtained. Heat the mixture and maintain the temperature for the reaction.

[0021] S34. 30 minutes before the end of the heat preservation reaction, add tannic acid slurry to the mixture B of S33, stir, and react.

[0022] Preferably, in step S31, the pre-emulsion obtained in step S1 is transferred to a reaction vessel, stirring is started at a speed of 150-200 rpm, nitrogen is continuously introduced into the reaction vessel, and the dissolved oxygen in the pre-emulsion is removed by bubbling for 20-30 minutes. After that, the bubbling is turned off, and a slight positive pressure is maintained in the reaction vessel. The gauge pressure in the reaction vessel is 0.02-0.05 MPa.

[0023] Preferably, in step S32, the hydrophilic monomer precomplex is added to the reactor and mixed with the preemulsion. The reactor is heated to 65-68°C and stirred at a speed of 150-200 rpm for 15-20 minutes.

[0024] Preferably, in S33, the dropping rate of the persulfate solution is 0.8-1.2% / min of the total volume of the persulfate solution, the dropping time is 1.5-2h, the dropping temperature is 65-68℃, and after the dropping is completed, the temperature is raised to 70-75℃ and the reaction is maintained at this temperature for 1-1.5h.

[0025] Preferably, in S34, before preparing the tannic acid slurry, the tannic acid is dried at 55-65℃ and vacuum degree ≤-0.095MPa for 4-4.5h to make the water content of the tannic acid ≤2.0%. Then, the dried tannic acid and deionized water are treated by a shear disperser at a mass ratio of 1:1.5 to prepare a uniform tannic acid slurry. After adding the tannic acid slurry, the stirring speed in the reaction vessel is 80-120rpm, the stirring time is 20-30min, and the stirring temperature is 70-75℃.

[0026] Preferably, in S4, the material is cooled to 20-25°C, and after vacuum degassing, it is sterilized by Co-60 γ-ray irradiation. The vacuum degree of vacuum degassing is -0.08~-0.1MPa, and the degassing time is 15-20min.

[0027] The present invention also provides an application of a medical sterile gel coupling agent, wherein the medical sterile gel coupling agent prepared by the aforementioned method is applied to ultrasound detection.

[0028] Furthermore, medical sterile gel coupling agents are used in clinical practice for anorectal, fistula, urological, and gynecological examinations. In ultrasound examinations, the gel coupling agent acts as a lubricant and an ultrasound medium.

[0029] Therefore, the present invention, by employing the above-mentioned preparation method and application of a medical sterile gel coupling agent, has the following beneficial effects:

[0030] (1) By controlling the particle size of latex particles (D90 < 2 μm) through pre-emulsification process, combined with the uniform network structure of in-situ composite polymerization, the sound velocity and acoustic impedance of the product are highly matched with human tissue and ultrasound probe, and the sound attenuation coefficient is ≤ 0.1 dB / cm·MHz, which is far superior to traditional coupling agent, effectively avoiding imaging artifacts and improving the accuracy of ultrasound diagnosis.

[0031] (2) By controlling the in-situ neutralization temperature of acrylic acid by HACC through an ice-water bath, the alkalinity of HACC is used to complete the partial neutralization, while avoiding premature polymerization of acrylic acid, thus ensuring the uniformity of the hydrophilic monomer precomplex. Compared with the process without temperature control, the product performance fluctuation is reduced by more than 80%.

[0032] (3) Using the chitosan quaternary ammonium salt inherent in the formula as an endogenous neutralizing agent, the acrylic acid is neutralized in situ, avoiding the introduction of exogenous substances such as sodium hydroxide, simplifying the formula, and improving the chemical purity and biological safety of the product.

[0033] (4) A hydrophilic monomer precomplex was prepared by a low-temperature controllable neutralization reaction, and emulsion copolymerization was carried out simultaneously with the oil phase monomer preemulsion under an inert atmosphere. Finally, tannic acid slurry was introduced for physical crosslinking. This process formed a unique chemical crosslinking + physical crosslinking dual stable structure.

[0034] (5) From the standardized pretreatment of raw materials, the precise temperature control of key steps, the strict protection of the reaction environment, to the adaptive sterilization of the terminal, each step has clear parameter control and quality nodes; the stark contrast between the examples and the comparative examples proves that the process is an inseparable organic whole, and the absence or deviation of any single link will directly lead to the complete failure of the product in terms of structural uniformity, functional effectiveness or chemical safety.

[0035] The technical solution of the present invention will be further described in detail below through embodiments. Detailed Implementation

[0036] The technical solution of the present invention will be further described below through embodiments.

[0037] Unless otherwise defined, the technical or scientific terms used in this invention shall have the ordinary meaning understood by one of ordinary skill in the art to which this invention pertains. If the absolute position of the described objects changes, the relative positional relationship may also change accordingly.

[0038] Example 1

[0039] This invention provides a medical sterile gel coupling agent, comprising the following raw materials by mass percentage: 7% acrylic acid (AA), 50% ethyl acrylate (EA), 20% butyl acrylate (BA), 2% AEO-15, 1.5% sodium dodecyl sulfate (SDS), 3% potassium persulfate (KPS), 7.5% tannic acid (TA), 5% chitosan quaternary ammonium salt (HACC), with the remainder made up with deionized water.

[0040] Its preparation method includes the following steps:

[0041] S1. Pre-emulsification: Dissolve AEO-15 and SDS in a portion of deionized water and stir at 300 rpm. Add EA and BA, increase the stirring speed to 3000 rpm, and homogenize for 12 min to obtain a stable pre-emulsion with an average particle size D90 = 1.5 μm.

[0042] S2, Endogenous Neutralization: The dried HACC (60℃, vacuum dried for 4h) was dissolved in a portion of deionized water. Under an ice-water bath and stirring at 600 rpm, AA was added dropwise to the HACC solution at a rate of approximately 2.5 mL / min, with the temperature controlled at 18℃ and the addition time at 25 min, to obtain a hydrophilic monomer precomplex (pH≈5.8).

[0043] S3, Simultaneous Composite Polymerization and Crosslinking:

[0044] S31. Transfer the pre-emulsion to the reactor, stir at 180 rpm and bubble with nitrogen for 25 min to remove oxygen, obtaining a deoxygenated pre-emulsion. Then maintain a slight positive pressure of 0.03 MPa. Oxygen (O2) is a highly efficient inhibitor of free radical polymerization. It readily combines with primary free radicals or chain-growing free radicals generated by the decomposition of the initiator to form low-activity (or inert) peroxy free radicals, thus severely hindering the chain initiation and chain growth processes. If the emulsion is not deoxygenated, the reaction induction period will be prolonged or even non-reactive, and the degree of polymerization will be low, the product viscosity will be low, and the strength will be poor.

[0045] Oxygen removal is achieved by nitrogen bubbling displacement. Before the reaction begins, high-purity nitrogen is continuously introduced for a period of time. The inert nitrogen bubbles pass through the liquid, physically carrying away the oxygen dissolved in the liquid, thus filling the reaction space with an inert atmosphere.

[0046] S32. Mix the deoxygenated pre-emulsion obtained in S31 and the hydrophilic monomer pre-complex obtained in S2, heat to 66℃, and stir stably for 10 min to obtain mixed system A.

[0047] S33. Add KPS aqueous solution dropwise to the mixed system A obtained in S32. The dropwise addition time is 1.8h, the rate is constant, about 1.0% / min, and the temperature is controlled at 68℃ during the dropwise addition. After the dropwise addition is completed, mixed system B is obtained. After the dropwise addition is completed, the temperature is raised to 72℃ and kept at this temperature for 1h.

[0048] S34. 30 minutes before the end of the heat preservation period, the dried TA and 40℃ deionized water are continuously mixed at a mass ratio of 1:1.5 using an online high-shear mixer to form a slurry, which is then added to the reactor within 10 minutes. After the addition is complete, the stirring speed is adjusted to 100 rpm, and the reaction continues at 72℃ for 25 minutes.

[0049] S4. Post-treatment: Cool to 23℃ and degas under a vacuum of -0.09MPa for 18 minutes. Fill into brown light-proof tubes, and after proper packaging, sterilize using Co-60 gamma irradiation at a dose of 8.0kGy. The purpose of vacuum degassing is to eliminate acoustic interference sources. In vacuum degassing, the pressure inside the dissolved gases (such as air and nitrogen) and microbubbles is greater than the external environmental pressure. According to Henry's Law and bubble dynamics, the gas solubility decreases, causing the bubbles to rapidly expand, merge, and, due to density differences, accelerate their rise to the surface and rupture.

[0050] Vacuum degassing tanks are used for degassing. The vacuum system consists of a vacuum pump (such as a rotary vane pump), vacuum pipelines, valves, and a vacuum gauge. Maintaining a vacuum level of -0.08 to -0.1 MPa is considered a low vacuum range, which does not place high demands on the pump and is the most common configuration in laboratories and workshops.

[0051] The slow-speed stirring system, equipped with anchor or frame-type stirring paddles, typically operates at 10-50 rpm. Its purpose is not mixing, but rather to slowly agitate the gel, helping internal air bubbles migrate to the surface and break, preventing gel bridging and avoiding the formation of vacuum dead zones.

[0052] Example 2

[0053] The only difference between this embodiment and Example 1 is that in S2, the temperature of the ice-water bath is adjusted to 10°C, the dropping time of acrylic acid is extended to 30 min, and the dropping rate is adjusted to approximately 1.9 mL / min. All other conditions are the same.

[0054] Example 3

[0055] The only difference between this embodiment and Embodiment 1 is that in S33, the polymerization reaction temperature is adjusted to 68°C and the crosslinking reaction temperature is adjusted to 75°C; all other conditions are the same.

[0056] Comparative Example 1

[0057] The only difference between this comparative example and Example 1 is that, in the S2 endogenous neutralization step, the ice-water bath cooling was omitted, and acrylic acid was added dropwise at room temperature. Because the neutralization reaction is exothermic, the system temperature rose to a maximum of 45°C during the dropwise addition process; all other conditions remained the same.

[0058] Comparative Example 2

[0059] The only difference between this comparative example and Example 1 is that, in S31 and subsequent polymerization processes, nitrogen protection and micro-positive pressure maintenance were completely eliminated. All operations, including deoxygenation, mixing, polymerization, and crosslinking, were carried out under open conditions (with condenser reflux but no inert atmosphere). All other conditions were the same.

[0060] Comparative Example 3

[0061] The only difference between this comparative example and Example 1 is that the timing and physical state of tannic acid (TA) were changed:

[0062] Timing: Add TA powder to the pre-emulsion along with the hydrophilic monomer pre-complex in S32, i.e., before polymerization begins. Method: Add TA directly as a dry powder without slurry preparation; all other conditions remain the same.

[0063] Comparative Example 4

[0064] The only difference between this comparative example and Example 1 is that in the S4 post-processing step, conventional high-pressure steam sterilization (121°C, 15 min) was used instead of Co-60 γ-ray irradiation sterilization; all other conditions were the same.

[0065] The medical sterile ultrasound coupling agents prepared in Examples 1-3 and Comparative Examples 1-4 of this invention were subjected to performance tests in accordance with the pharmaceutical industry standard YY0299-2016 "Medical Ultrasonic Coupling Agents". The test results are shown in Table 1.

[0066] Table 1 Test Results

[0067]

[0068] As shown in Table 1, the sound velocity and acoustic impedance of Examples 1-3 are all within the range of the YY0299-2016 standard (sound velocity 1520-1620 m / s, acoustic impedance 1.5-1.7 × 10⁻⁶). 6The sound attenuation is ≤0.1dB / cm·MHz, meeting the needs of clinical ultrasound imaging.

[0069] Comparative Example 1 suffered from premature polymerization of acrylic acid due to excessively high neutralization temperature, resulting in acoustic parameters deviating from the optimal range. Comparative Examples 2 and 4 suffered from excessive acoustic parameters due to process defects, which could not guarantee image clarity.

[0070] The viscosity (32-38 Pa·s) of Examples 1-3 meets the coating requirements of medical coupling agents, and the pH value is close to that of human skin (5.5-8.0).

[0071] The viscosity of Comparative Examples 1 and 4 decreased significantly, while the pH value of Comparative Example 1 was too low, which could easily irritate the skin.

[0072] Examples 1-3 and Comparative Examples 1, 3 and 4 all met the aseptic requirements, but Comparative Example 2 did not meet the aseptic standard because contaminating bacteria were introduced due to open operation; although the high-temperature sterilization of Comparative Example 4 achieved asepticity, it damaged the gel properties.

[0073] Examples 1-3 and Comparative Examples 1 and 3 were tested according to GB / T 21866-2008 "Determination of Antibacterial Properties and Antibacterial Effects of Antibacterial Coatings (Films)" and the test results are shown in Table 2.

[0074] Table 2 Test Results

[0075]

[0076] As shown in Table 2, the 24-hour antibacterial rates of Examples 1-3 against Staphylococcus aureus (representative of Gram-positive bacteria) and Escherichia coli (representative of Gram-negative bacteria) were all >99.9%. This indicates that the gel coupling agent prepared in this scheme has strong and broad-spectrum antibacterial properties.

[0077] The high antibacterial rates of Examples 1-3 are a result of the synergistic effect of chitosan quaternary ammonium salt and tannic acid in the formulation achieved through the specific process of this invention. HACC disrupts bacterial cell membranes through positive charge, while TA penetrates into the cell to inhibit enzyme activity, forming a highly efficient combination of membrane disruption and killing. The minor fluctuations between the examples are within the experimental error range, demonstrating that this excellent performance can be stably reproduced within the process parameter window described in the claims.

[0078] Comparative Example 1 showed an antibacterial rate decrease to approximately 90%. This significant decrease demonstrates the loss of control over the low-temperature endogenous neutralization step, disrupting the process by which HACCP and AA form a homogeneous and stable pre-complex. This may lead to:

[0079] The uneven distribution of HACC in the final gel and the insufficient concentration in some areas; the weak binding of HACC to the polymer network and partial failure; ultimately affecting the synergistic efficiency of HACC with TA, resulting in a significant reduction in antibacterial properties.

[0080] Comparative Example 3 (incorrect timing and method of TA addition) showed an antibacterial rate decrease to approximately 92%. This result demonstrates that the specific step of introducing TA in slurry form during the later stages of polymerization is crucial; adding TA in dry powder form earlier will result in:

[0081] Interference with polymerization: The polyphenolic structure of TA may act as a polymerization inhibitor or chain transfer agent, affecting the complete formation of the polymer network; Uneven dispersion: The dry powder is difficult to disperse evenly in a viscous system, which makes it impossible for TA to effectively form physical cross-linking points and antibacterial sites throughout the entire network;

[0082] Functional limitations: The TA that is encapsulated or aggregated cannot fully contact and act on bacteria, thus its antibacterial potential cannot be realized;

[0083] The data from Comparative Examples 1 and 3 clearly demonstrate that any operation that deviates from the core process steps of this invention (low-temperature endogenous neutralization and subsequent slurry crosslinking), even when using the exact same raw materials, will lead to a significant deterioration of the core antibacterial function. This strongly proves the non-obviousness and indivisibility of the process steps.

[0084] A comparison with traditional products highlights the breakthrough nature of this invention: the antibacterial rate of the conventional coupling agent, used as a control, is <50%, a stark contrast to the examples; conventional coupling agents typically function only as acoustic media, possessing little or no antibacterial function. This invention, through innovative formulation and process, successfully integrates potent antibacterial functionality into the coupling agent, achieving a qualitative leap from passive sound conduction to active protection. This comparison underscores the groundbreaking progress and significant clinical application value of this invention.

[0085] Therefore, the present invention adopts the above-mentioned preparation method and application of a medical sterile gel coupling agent. Through the endogenous neutralization-synchronous composite integrated process, the powerful antibacterial and tissue repair functions are deeply integrated into a stable gel network. This process enables the key active ingredients to produce a structure-function synergy effect, forming an inseparable precision system. The final product achieves active antibacterial protection while maintaining excellent imaging performance, and has excellent biocompatibility.

[0086] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can still be made to the technical solutions of the present invention, and these modifications or equivalent substitutions cannot cause the modified technical solutions to deviate from the spirit and scope of the technical solutions of the present invention.

Claims

1. A method for preparing a sterile medical gel coupling agent, wherein the sterile medical gel coupling agent comprises, by mass fraction, the following raw materials: 6%-8% acrylic acid, 50%-70% ethyl acrylate, 20%-30% butyl acrylate, 1%-3% AEO-15, 1%-2% sodium dodecyl sulfonate, 3%-5% persulfate, 5%-10% tannic acid, 2%-8% chitosan quaternary ammonium salt, with the remainder made up by deionized water, characterized in that: Includes the following steps: S1. Pre-emulsification: Dissolve AEO-15 and sodium dodecyl sulfonate in deionized water and stir, then add ethyl acrylate and butyl acrylate and stir to obtain a pre-emulsion. S2. Prepare a chitosan quaternary ammonium salt aqueous solution by adding acrylic acid to the chitosan quaternary ammonium salt aqueous solution and stirring to obtain a hydrophilic monomer precomplex. In S2, acrylic acid is slowly added dropwise to the chitosan quaternary ammonium salt aqueous solution through a constant pressure dropping funnel or metering pump under the cooling of ice water bath at 500-700 rpm. During the dropwise addition, the temperature of the reaction system is maintained between 10-20℃, and the total dropwise addition time is controlled within 20-30 min, with a dropwise addition rate of 2-3 mL / min. S3. Add the pre-emulsion obtained in S1 and the hydrophilic monomer pre-complex obtained in S2 into the reactor, and add persulfate solution dropwise to react. After the reaction, add tannic acid slurry and stir. The specific operation of S3 is as follows: S31. Deoxygenate the pre-emulsion to obtain a deoxygenated pre-emulsion; S32. Mix the deoxygenated pre-emulsion obtained in S31 and the hydrophilic monomer pre-complex obtained in S2, heat and stir to obtain mixed system A; S33. Add persulfate solution dropwise to the mixed system A obtained in S32. After the addition is complete, mixed system B is obtained. Heat the system and maintain the temperature for the reaction. S34. 30 minutes before the end of the heat preservation reaction, add tannic acid slurry to the mixture B of S33, stir, and react. In S34, the tannic acid slurry is prepared by processing dried tannic acid and deionized water in a mass ratio of 1:1.5 using a shear disperser. After the stirring reaction in S4 and S3 is completed, the mixture is cooled and sterilized to obtain a sterile medical gel coupling agent; In S4, after cooling to 20-25℃, vacuum degassing and packaging are performed, and then sterilization is carried out by Co-60 γ-ray irradiation. The vacuum degree of vacuum degassing is -0.08~-0.1MPa, and the degassing time is 15-20min.

2. The method for preparing a sterile medical gel coupling agent according to claim 1, characterized in that: In S1, when AEO-15 and sodium dodecyl sulfonate are dissolved in deionized water, the stirring speed is 200-400 rpm and the mixture is stirred until completely dissolved. After adding ethyl acrylate and butyl acrylate, the stirring speed is 2500-3500 rpm and the stirring time is 10-15 min.

3. The method for preparing a medical sterile gel coupling agent according to claim 1, characterized in that: In S2, before preparing the chitosan quaternary ammonium salt aqueous solution, the chitosan quaternary ammonium salt is dried at a temperature of 55-65℃ for 4-4.5 hours. The vacuum degree during drying is ≤-0.095MPa, and the water content of the dried chitosan quaternary ammonium salt is ≤2.0%.

4. The method for preparing a medical sterile gel coupling agent according to claim 1, characterized in that: In step S31, the pre-emulsion obtained in step S1 is transferred to a reactor, and stirring is started at a speed of 150-200 rpm. Nitrogen gas is continuously introduced into the reactor, and the mixture is bubbled for 20-30 minutes to remove dissolved oxygen from the pre-emulsion. After that, the bubbling is turned off, and a slight positive pressure is maintained in the reactor. The gauge pressure in the reactor is 0.02-0.05 MPa.

5. The method for preparing a sterile medical gel coupling agent according to claim 1, characterized in that: In S32, the hydrophilic monomer precomplex is added to the reactor and mixed with the preemulsion. The reactor is heated to 65-68℃ and stirred at a speed of 150-200 rpm for 15-20 minutes.

6. The method for preparing a sterile medical gel coupling agent according to claim 1, characterized in that: In S33, the dropping rate of the persulfate solution is 0.8-1.2% / min of the total volume of the persulfate solution, the dropping time is 1.5-2h, the dropping temperature is 65-68℃, and after the dropping is completed, the temperature is raised to 70-75℃ and the reaction is maintained at this temperature for 1-1.5h.

7. The method for preparing a sterile medical gel coupling agent according to claim 1, characterized in that: In S34, before preparing the tannic acid slurry, the tannic acid is dried at 55-65℃ and vacuum degree ≤-0.095MPa for 4-4.5h to make the water content of the tannic acid ≤2.0%. Then, the dried tannic acid and deionized water are treated by a shear disperser at a mass ratio of 1:1.5 to prepare a uniform tannic acid slurry. After adding the tannic acid slurry, the stirring speed in the reaction vessel is 80-120rpm, the stirring time is 20-30min, and the stirring temperature is 70-75℃.

8. The application of a sterile medical gel coupling agent, characterized in that: The sterile medical gel coupling agent prepared by the method of any one of claims 1-7 is used in the preparation of ultrasound examination reagents.

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