Absorbable disinfection ultrasonic coupling agent and preparation method thereof

Abstract

The invention relates to the technical field of ultrasonic coupling agent preparation, and discloses an absorbable and disinfected ultrasonic coupling agent and a preparation method thereof.The preparation method comprises the following steps that a gel forming matrix is prepared, specifically, a temperature-sensitive gel precursor, a trehalose derivative and a water-soluble polymer are selected and evenly mixed in a sterile environment; disinfection treatment: loading a disinfection active component on mesoporous silicon dioxide nanoparticles, and adding the mesoporous silicon dioxide nanoparticles into a gel-forming matrix through ultrasonic dispersion; and activating the functional synergist. A temperature-sensitive gel precursor in the gelling matrix spontaneously forms a three-dimensional network structure at the physiological temperature, the disinfection active component is wrapped, instant phase change curing of the coupling agent is achieved, and the adhesive force of the ultrasonic probe is improved; the trehalose derivative enhances the stability of a gel network through a hydrophobic association effect, and cooperates with the water-soluble polymer to construct a dynamic molecular barrier to block sudden release of disinfection components, so that the durability and controllability of the sterilization efficiency are ensured.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of ultrasonic coupling agent preparation, in particular to an absorbable and sterilizable ultrasonic coupling agent and a preparation method thereof. BACKGROUND

[0002] The medical coupling agent is a medical product composed of a new generation of water-based polymer gel, and has neutral pH value, no toxicity and harm to human body, no easy drying, no easy rancidity, clear ultrasonic imaging, appropriate viscosity, no greasy, easy probe sliding, can wet the skin, eliminate the air on the skin surface, good lubricity, easy to spread and no corrosion and damage to the ultrasonic probe; in medical ultrasonic diagnosis, due to the strong reflection of the air layer between the probe and the skin, the ultrasonic wave cannot reach and enter the human body, so the medical ultrasonic coupling agent must be filled between the probe surface and the skin to remove the air and form a channel for smooth and distortionless transmission of ultrasonic wave.

[0003] At present, due to the limitation of compatibility of ultrasonic coupling agent components, when the sterilization function of the coupling agent is realized, the active sterilization component and the gel matrix cannot form a stable dispersion system, and when the sterilization agent is locally aggregated and precipitated, the uneven distribution of sterilization efficiency will occur, which cannot guarantee the reliability and durability of the sterilization effect.

[0004] Therefore, the present application provides an absorbable and sterilizable ultrasonic coupling agent and a preparation method thereof to solve the above problems. SUMMARY

[0005] In view of the deficiencies of the prior art, the present application provides an absorbable and sterilizable ultrasonic coupling agent and a preparation method thereof, which solves the problem of uneven distribution of sterilization efficiency and the problem of inability to guarantee the reliability and durability of the sterilization effect.

[0006] To achieve the above purpose, the present application provides the following technical scheme: an absorbable and sterilizable ultrasonic coupling agent and a preparation method thereof, comprising the following steps: Step one: gel matrix preparation, selecting temperature-sensitive gel precursor, trehalose derivative and water-soluble polymer, and mixing uniformly in a sterile environment; Step two: sterilization treatment, loading the sterilization active ingredient on mesoporous silica nanoparticles, and adding into the gel matrix by ultrasonic dispersion; Step three: functional synergist activation, plasma treatment of the absorbable enhancement component; Step four: coupling agent synthesis, mixing the sterilized gel matrix and the activated functional synergist, and gradient temperature reaction and cooling filling after reaction; The functional synergist in step three is made of the following raw materials by weight: nano-silver sol 5-15 parts, chitosan quaternary ammonium salt 10-20 parts, lysozyme 3-8 parts, and absorbable buffer 5-10 parts. The disinfecting active ingredient in step two is a compound of biguanide disinfectant and iodophor, and the mass ratio of biguanide disinfectant to iodophor is 1:0.5-1:2.

[0007] Preferably, step one comprises: The temperature-sensitive gel precursor is placed in a sterile reaction kettle, the temperature is controlled at 4-8℃, and the temperature-sensitive gel precursor is dissolved in water for injection by stirring at 200-500 r / min. The trehalose derivative is continuously added, and after dissolution, the water-soluble polymer is added, and the stirring is maintained for 30-60 min. The temperature-sensitive gel precursor is poloxamer 407, the trehalose derivative is trehalose laurate, and the water-soluble polymer is at least one of sodium hyaluronate or sodium carboxymethyl cellulose.

[0008] Preferably, the mass ratio of poloxamer 407, trehalose laurate and water-soluble polymer is 15-25:5-10:1-3, wherein the concentration of poloxamer 407 is 18-22 wt%, and the degree of substitution of trehalose laurate is 0.8-1.2.

[0009] Preferably, step two comprises: The mesoporous silica nanoparticles are placed in a vacuum impregnation tank, vacuumed to 0.01-0.05 kPa, and then the mixed solution of biguanide disinfectant and iodophor is injected. After 2-4 h of impregnation, centrifugal separation is performed to obtain nanoparticles loaded with disinfecting active ingredients. The nanoparticles are added to the gel-forming matrix, and ultrasonic dispersion is performed at 20-40 kHz under ice bath conditions for 15-30 min. The pore size of the mesoporous silica nanoparticles is 5-10 nm, and the specific surface area is ≥800 m² / g.

[0010] Preferably, step three comprises: The nano-silver sol, chitosan quaternary ammonium salt, lysozyme and absorbable buffer are placed in a plasma reaction chamber, vacuumed to 1× -1× Pa, argon gas is introduced to increase the pressure to 50-100 Pa, and the treatment is performed at a power of 200-400 W for 5-15 min. The absorbable buffer is composed of sodium citrate and sodium bicarbonate at a mass ratio of 2:1, and the particle size of the functional synergist after plasma treatment is 80-150 nm.

[0011] Preferably, step four comprises: The functional enhancer is added into the gelling base after disinfection treatment, mixed by stirring at 100-300 r / min, the temperature is raised from 4℃ to 25℃ at a rate of 1℃ / min, then raised to 37℃ at a rate of 0.5℃ / min, after constant temperature reaction for 1-2 h, it is cooled to 4-8℃ for filling; The gradient temperature process is carried out in a self-foaming closed reactor, and the pressure in the reactor is maintained at 0.5-0.8 MPa.

[0012] Preferably, the final concentration of the absorbable buffer in the coupling agent is 0.1-0.5 mol / L, and the pH value is adjusted to 6.8-7.2; The mass ratio of the gelling base to the functional enhancer is 8:1-5:1.

[0013] Preferably, the coupling agent comprises the following components by weight percentage: Temperature-sensitive gel base 60-75%; Disinfectant active ingredient carrier 10-18%; Functional enhancer 15-25%; The viscosity of the coupling agent is 8000-15000 cP, the conductivity is ≤20 μS / cm, and the skin absorption rate at 37℃ is ≥95% / 30 min.

[0014] Preferably, the disinfectant active ingredient carrier is polyhexamethylene biguanide hydrochloride, the concentration is 0.2-0.8 wt%, and the iodophor is polyvinylpyrrolidone iodine, the effective iodine content is 0.05-0.2 wt%; The particle size of nano-silver in the functional enhancer is 10-30 nm, and the concentration is 50-100 ppm.

[0015] Preferably, the storage stability of the coupling agent at 4-25℃ is ≥12 months, the phase transition temperature is 33-35℃, the ultrasonic attenuation coefficient is ≤0.5 dB / (cm·MHz), and the acoustic impedance matching range is 1.4-1.6× Pa·s / m.

[0016] Compared with the prior art, the present application provides an absorbable disinfecting ultrasonic coupling agent and a preparation method thereof, which has the following beneficial effects: 1. In the present application, the temperature-sensitive gel precursor in the gel-forming matrix spontaneously forms a three-dimensional network structure at physiological temperature, encapsulates the disinfecting active ingredient, realizes the instant phase change solidification of the coupling agent, and improves the adhesion of the ultrasonic probe; the trehalose derivative enhances the stability of the gel network through hydrophobic association, cooperates with the water-soluble polymer to construct a dynamic molecular barrier, and blocks the burst release of the disinfecting ingredient, thereby ensuring the persistence and controllability of the bactericidal efficacy; at the same time, the functional synergist improves the surface energy after plasma activation, forms a dual mechanism of chemical bonding and physical entanglement with the gel network, reduces the risk of component interface separation, avoids the irritant reaction caused by local abnormal concentration, and strengthens the biocompatibility of the coupling agent.

[0017] 2. In the present application, in the disinfection treatment step, the mesoporous silica nanoparticles realize the gradient loading and slow release of the biguanide disinfectant and iodophor through the molecular-scale pore confinement effect; the surface silicon hydroxyl group forms a directional diffusion channel with the hydrogen bond of the gel-forming matrix, so that the disinfecting ingredient is released on demand when contacting the body fluid; at the same time, the organic silicon skeleton can be gradually hydrolyzed during the absorption of the coupling agent, generating a biocompatible silanol compound, which cooperates with the positive electric property of the chitosan quaternary ammonium salt to neutralize the negative charge on the surface of the pathogenic microorganism, thereby disrupting the integrity of the cell membrane at the molecular level, constructing an efficient and self-terminating sterilization system, expanding the antibacterial spectrum, and cooperating with the pH buffering capacity of the absorbable buffer to maintain the stability of the tissue microenvironment.

[0018] 3. In the present application, when designing the functional synergist, the surface defect sites generated by the plasma excitation of the nano-silver sol form coordination bonding with the peptide bond of lysozyme, enhancing its targeted hydrolysis ability to bacterial cell walls; the citrate in the absorbable buffer seamlessly connects with the tricarboxylic acid cycle metabolic pathway in the human body, actively mediating the absorption process through transmembrane transport proteins; at the same time, the cationic groups of the chitosan quaternary ammonium salt activate the hydration of the mucus layer in the body fluid environment, accelerating the disintegration of the gel network into metabolizable fragments, realizing the simultaneous degradation and removal of the coupling agent residue at the molecular level, and improving the safety and patient comfort of clinical operation. BRIEF DESCRIPTION OF DRAWINGS

[0019] Figure 1 The present application is a whole flow chart of an absorbable disinfecting ultrasonic coupling agent. DETAILED DESCRIPTION

[0020] The technical solutions in the embodiments of the present application will be described clearly and completely below with reference to the drawings in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0021] Embodiment one, an absorbable and sterilizable ultrasonic coupling agent and a preparation method thereof, comprising the following steps: Step one: gel base preparation, select temperature-sensitive gel precursor, trehalose derivative and water-soluble polymer, mix uniformly in a sterile environment; Step two: sterilization treatment, load the sterilization active ingredient on mesoporous silica nanoparticles, and add to the gel base by ultrasonic dispersion; Step three: functional synergist activation, plasma treatment of absorbable enhancement components; Step four: coupling agent synthesis, mix the sterilized gel base with the activated functional synergist, gradient temperature reaction and then cool and fill; In step three, the functional synergist is made of the following raw materials by weight: 5 parts of nano-silver sol, 10 parts of chitosan quaternary ammonium salt, 3 parts of lysozyme, and 5 parts of absorbable buffer; The sterilization active ingredient in step two is a compound of biguanide disinfectant and iodophor, and the mass ratio of biguanide disinfectant to iodophor is 1:0.5.

[0022] Step one includes: Put the temperature-sensitive gel precursor into a sterile reaction kettle, control the temperature at 4℃, dissolve in water for injection at 200r / min stirring, continuously add trehalose derivative, and then add water-soluble polymer, maintain stirring for 30min; The temperature-sensitive gel precursor uses poloxamer 407, the trehalose derivative uses trehalose laurate, and the water-soluble polymer uses at least one of sodium hyaluronate or sodium carboxymethyl cellulose.

[0023] The mass ratio of poloxamer 407, trehalose laurate and water-soluble polymer is 15:5:1, wherein the concentration of poloxamer 407 is 18wt%, and the degree of substitution of trehalose laurate is 0.8.

[0024] Step two includes: Put the mesoporous silica nanoparticles into a vacuum impregnation tank, vacuum to 0.01kPa, then inject the mixed solution of biguanide disinfectant and iodophor, centrifuge after impregnation for 2h, get the nanoparticles loaded with sterilization active ingredient, add the nanoparticles to the gel base, and ultrasonically disperse for 15min under ice bath condition at 20kHz; The pore size of the mesoporous silica nanoparticles is 5nm, and the specific surface area is ≥800m² / g.

[0025] Step three includes: Put the nano-silver sol, chitosan quaternary ammonium salt, lysozyme and absorbable buffer into the plasma reaction cavity, vacuum to 1× Pa, introduce argon to make the pressure rise to 50Pa, and treat for 5min at a power of 200W; The absorbable buffer is composed of sodium citrate and sodium bicarbonate in a mass ratio of 2:1, and the particle size of the functional enhancer after plasma treatment is 80 nm.

[0026] Step four includes: The functional enhancer is added to the gel-forming base after sterilization treatment, mixed by stirring at 100 r / min, and heated from 4°C to 25°C at a rate of 1°C / min, and then heated to 37°C at a rate of 0.5°C / min. After 1 h of constant temperature reaction, it is cooled to 4°C for filling; The gradient heating process is carried out in a self-foaming closed reactor, and the pressure in the reactor is maintained at 0.5 MPa.

[0027] The final concentration of the absorbable buffer in the coupling agent is 0.1 mol / L, and the pH value is adjusted to 6.8; The mass ratio of the gel-forming base to the functional enhancer is 8:1.

[0028] The coupling agent contains the following components by weight percentage: Temperature-sensitive gel base 60%; Disinfectant active ingredient carrier 10%; Functional enhancer 15%; The viscosity of the coupling agent is 8000 cP, the conductivity is ≤20 μS / cm, and the skin absorption rate is ≥95% / 30 min at 37°C.

[0029] The biguanide disinfectant in the disinfectant active ingredient carrier is polyhexamethylene biguanide hydrochloride, with a concentration of 0.2 wt%, and the iodophor is polyvinylpyrrolidone iodine, with an effective iodine content of 0.05 wt%; The particle size of nano-silver in the functional enhancer is 10 nm, and the concentration is 50 ppm.

[0030] The storage stability of the coupling agent at 4°C is ≥12 months, the phase transition temperature is 33°C, the ultrasonic attenuation coefficient is ≤0.5 dB / (cm·MHz), and the acoustic impedance is 1.4× Pa·s / m.

[0031] Example two, an absorbable disinfecting ultrasonic coupling agent and a preparation method thereof, comprising the following steps: Step one: gel-forming base preparation, select temperature-sensitive gel precursor, trehalose derivative and water-soluble polymer, mix uniformly in a sterile environment; Step two: sterilization treatment, load the disinfectant active ingredient on the mesoporous silica nanoparticles, and add it to the gel-forming base by ultrasonic dispersion; Step three: functional enhancer activation, plasma treatment of absorbable enhancement components; Step four: coupling agent synthesis, sterilized gel-forming base mixed with activated functional synergist, gradient temperature reaction and cooling filling; In step three, the functional synergist is made from the following raw materials by weight: 10 parts of nano-silver sol, 15 parts of chitosan quaternary ammonium salt, 5 parts of lysozyme, and 8 parts of absorbable buffer. In step two, the sterilized active ingredient is a compound of a biguanide disinfectant and iodophor, and the mass ratio of the biguanide disinfectant to iodophor is 1:1.

[0032] Step one includes: The temperature-sensitive gel precursor is placed in a sterile reaction kettle, the temperature is controlled at 6°C, and it is dissolved in water for injection with stirring at 300 r / min. The trehalose derivative is continuously added, and after dissolution, the water-soluble polymer is added. Stirring is maintained for 45 min. The temperature-sensitive gel precursor is poloxamer 407, the trehalose derivative is trehalose laurate, and the water-soluble polymer is at least one of sodium hyaluronate or sodium carboxymethyl cellulose.

[0033] The mass ratio of poloxamer 407, trehalose laurate, and water-soluble polymer is 20:8:2, wherein the concentration of poloxamer 407 is 20 wt%, and the degree of substitution of trehalose laurate is 1.0.

[0034] Step two includes: The mesoporous silica nanoparticles are placed in a vacuum impregnation tank, vacuumed to 0.03 kPa, and then the mixed solution of biguanide disinfectant and iodophor is injected. After 3 h of immersion, centrifugal separation is performed to obtain nanoparticles loaded with sterilization active ingredients. The nanoparticles are added to the gel-forming base, and ultrasonic dispersion is performed at 30 kHz for 20 min under ice bath conditions. The pore size of the mesoporous silica nanoparticles is 8 nm, and the specific surface area is ≥800 m² / g.

[0035] Step three includes: The nano-silver sol, chitosan quaternary ammonium salt, lysozyme, and absorbable buffer are placed in a plasma reaction chamber, vacuumed to 1× Pa, argon gas is introduced to increase the pressure to 80 Pa, and plasma treatment is performed at a power of 300 W for 10 min. The absorbable buffer is composed of sodium citrate and sodium bicarbonate at a mass ratio of 2:1, and the particle size of the functional synergist after plasma treatment is 120 nm.

[0036] Step four includes: The functional synergist is added to the sterilized gel-forming base, stirred at 200 r / min, and heated from 4°C to 25°C at a rate of 1°C / min, then heated to 37°C at a rate of 0.5°C / min. After constant temperature reaction for 1.5 h, cooling to 6°C for filling; The gradient temperature process is carried out in a self-foaming closed reactor, and the pressure in the reactor is maintained at 0.6 MPa.

[0037] The final concentration of the absorbable buffer in the coupling agent is 0.3 mol / L, and the pH value is adjusted to 7.0; The mass ratio of the gel-forming base to the functional synergist is 6:1.

[0038] The coupling agent contains the following components by weight percentage: The temperature-sensitive gel-forming base is 70%; The disinfectant active ingredient carrier is 15%; The functional synergist is 20%; The viscosity of the coupling agent is 12000 cP, the conductivity is ≤20 μS / cm, and the skin absorption rate at 37℃ is ≥95% / 30 min.

[0039] The biguanide disinfectant in the disinfectant active ingredient carrier is polyhexamethylene biguanide hydrochloride, with a concentration of 0.5 wt%, and the iodophor is polyvinylpyrrolidone iodine, with an effective iodine content of 0.1 wt%; The nano-silver particle size in the functional synergist is 20 nm, and the concentration is 70 ppm.

[0040] The storage stability of the coupling agent at 15℃ is ≥12 months, the phase transition temperature is 34℃, the ultrasonic attenuation coefficient is ≤0.5 dB / (cm·MHz), and the acoustic impedance is 1.5× Pa·s / m.

[0041] Example Three, an absorbable disinfectant ultrasonic coupling agent and a preparation method thereof, comprising the following steps: Step One: Preparation of the gel-forming base, select a temperature-sensitive gel precursor, a trehalose derivative, and a water-soluble polymer, and mix them uniformly in a sterile environment; Step Two: Disinfection, load the disinfectant active ingredient on mesoporous silica nanoparticles, and add them to the gel-forming base by ultrasonic dispersion; Step Three: Activation of the functional synergist, plasma treatment of the absorbable enhancement component; Step Four: Synthesis of the coupling agent, mix the disinfectant-treated gel-forming base with the activated functional synergist, and cool and fill after gradient temperature reaction; In Step Three, the functional synergist is made from the following raw materials by weight: nano-silver sol 15 parts, chitosan quaternary ammonium salt 20 parts, lysozyme 8 parts, and absorbable buffer 10 parts; In Step Two, the disinfectant active ingredient is a compound of biguanide disinfectant and iodophor, and the mass ratio of biguanide disinfectant to iodophor is 1:2.

[0042] Step One includes: The temperature-sensitive gel precursor is placed in a sterile reaction kettle, the temperature is controlled at 8℃, and stirring is carried out at 500 r / min in water for injection, and the trehalose derivative is continuously added, and after dissolving, the water-soluble polymer is added, and the stirring is maintained for 60 min; The temperature-sensitive gel precursor is poloxamer 407, the trehalose derivative is trehalose laurate, and the water-soluble polymer is at least one of sodium hyaluronate or sodium carboxymethyl cellulose.

[0043] The mass ratio of poloxamer 407, trehalose laurate and water-soluble polymer is 25:10:3, wherein the concentration of poloxamer 407 is 22wt%, and the degree of substitution of trehalose laurate is 1.2.

[0044] Step two includes: The mesoporous silica nanoparticles are placed in a vacuum impregnation tank, vacuumed to 0.05 kPa, and then the mixed solution of biguanide disinfectant and iodophor is injected, and after impregnation for 4 h, centrifugal separation is carried out, and the nanoparticles loaded with disinfection active ingredients are obtained, and the nanoparticles are added to the gelation matrix, and ultrasonic dispersion is carried out at 40 kHz under ice bath conditions for 30 min; The pore size of the mesoporous silica nanoparticles is 10 nm, and the specific surface area is ≥800 m² / g.

[0045] Step three includes: The nanosilver sol, chitosan quaternary ammonium salt, lysozyme and absorbable buffer are placed in a plasma reaction cavity, vacuumed to 1× Pa, argon gas is introduced to increase the pressure to 100 Pa, and the power is 400 W for 15 min; The absorbable buffer is composed of sodium citrate and sodium bicarbonate at a mass ratio of 2:1, and the particle size of the functional synergist after plasma treatment is 150 nm.

[0046] Step four includes: The functional synergist is added to the gelation matrix after disinfection treatment, and the mixture is stirred at 300 r / min, and the temperature is increased from 4℃ to 25℃ at a rate of 1℃ / min, and then increased to 37℃ at a rate of 0.5℃ / min, and then cooled to 8℃ for filling after constant temperature reaction for 2 h; The gradient temperature rising process is carried out in a self-foaming closed reactor, and the pressure in the reactor is maintained at 0.8 MPa.

[0047] The final concentration of the absorbable buffer in the coupling agent is 0.5 mol / L, and the pH value is adjusted to 7.2; The mass ratio of the gelation matrix to the functional synergist is 5:1.

[0048] The coupling agent contains the following components by weight percentage: Temperature-sensitive gel matrix 75%; Disinfectant active ingredient carrier 18%; Functional synergist 25%; The viscosity of the coupling agent is 15000 cP, the conductivity is ≤20 μS / cm, and the skin absorption rate is ≥95% / 30 min at 37℃.

[0049] The biguanide disinfectant in the disinfectant active ingredient carrier is polyhexamethylene biguanide hydrochloride, with a concentration of 0.8wt%, and the iodophor is polyvinylpyrrolidone iodine, with an effective iodine content of 0.2wt%; The particle size of the nano-silver in the functional synergist is 30 nm, and the concentration is 100 ppm.

[0050] The storage stability of the coupling agent at 25℃ is ≥12 months, the phase transition temperature is 35℃, the ultrasonic attenuation coefficient is ≤0.5 dB / (cm·MHz), and the acoustic impedance is 1.6× Pa·s / m.

[0051] Comparative Example 1, the difference between this comparative example and Example 1 is that no trehalose derivative is added when preparing the gel matrix.

[0052] Comparative Example 2, the difference between this comparative example and Example 1 is that mesoporous silica nanoparticle loaded disinfectant active ingredient is not used in the disinfection process.

[0053] Comparative Example 3, the difference between this comparative example and Example 1 is that the functional synergist is not subjected to plasma treatment.

[0054] Comparative Example 4, the difference between this comparative example and Example 1 is that no absorbable buffer is added in the synthesis of the coupling agent.

[0055] The absorbable disinfecting ultrasonic coupling agents prepared in Examples 1-3 and Comparative Examples 1-4 are subjected to performance testing, and the test items and test methods are as follows: Disinfection efficiency test, under the conditions of inoculating bacteria liquid concentration 1×10 8 CFU / mL, action time 1 / 5 / 10 min, taking 0.1 mL of the sample and coating it on the surface of the bacterial membrane, neutralizing to terminate the reaction, pouring nutrient agar, and calculating the reduction logarithm of viable bacteria at each time period.

[0056] Acoustic performance test, using the pulse reflection method, under the conditions of probe frequency 5 MHz and temperature 37±0.5℃, measuring the attenuation value and acoustic velocity fluctuation value of ultrasonic waves propagating 1 cm in the sample, and calculating the acoustic attenuation coefficient and acoustic impedance matching degree.

[0057] Skin absorption test, take the ex vivo human skin tissue, thickness 0.5±0.1mm, in the Franz diffusion cell 37℃ constant temperature environment, 0.2g of the sample is evenly coated on the epidermis layer, and the receiving pool liquid is collected at 5 / 30 / 60min time points to calculate the cumulative transdermal absorption rate.

[0058] Adhesion stability test, using a texture analyzer, under the conditions of probe inclination angle 45° and moving speed 1mm / s, the critical shear force of the sample sliding off 50% mass from the inclined skin model is measured, and the steady-state adhesion duration is calculated.

[0059] The test data of the absorbable disinfecting ultrasonic coupling agent prepared in examples 1-3 and comparative examples 1-4 are recorded in the following table: By comparing and analyzing the data in the table, it can be seen that the absorbable disinfecting ultrasonic coupling agent prepared by the process of examples 1-3 has significantly improved comprehensive performance compared with the ultrasonic coupling agent prepared by comparative examples 1-4, which indicates that the temperature-sensitive gel precursor in the gel-forming matrix spontaneously forms a three-dimensional network structure at physiological temperature, encapsulates the disinfecting active ingredients, realizes the instant phase change solidification of the coupling agent, and enhances the adhesion of the ultrasonic probe; the trehalose derivative enhances the stability of the gel network through hydrophobic association, and cooperates with the water-soluble polymer to construct a dynamic molecular barrier to block the burst release of the disinfecting ingredients, thereby ensuring the persistence and controllability of the sterilization efficiency; at the same time, the functional synergist enhances the surface energy after plasma activation, forms a dual mechanism of chemical bonding and physical entanglement with the gel network, reduces the risk of interface separation of the ingredients, avoids the irritant reaction caused by local abnormal concentration, and strengthens the biocompatibility of the coupling agent. In the disinfection process, mesoporous silica nanoparticles realize the gradient loading and slow release of biguanide and iodophor through the molecular-scale pore confinement effect; the surface silicon hydroxyl group forms a directional diffusion channel with the hydrogen bond of the gel-forming matrix, so that the disinfecting ingredients are released on demand when they come into contact with body fluid; at the same time, the organic silicon skeleton can be gradually hydrolyzed during the absorption of the coupling agent to generate biocompatible silanol compounds, which cooperate with the positive charge characteristics of chitosan quaternary ammonium salt to neutralize the negative charge on the surface of pathogenic microorganisms, thereby disrupting the integrity of the cell membrane at the molecular level and constructing an efficient and self-terminating sterilization system that expands the range of antibacterial spectrum and cooperates with the pH buffering capacity of the absorbable buffer to maintain the stability of the tissue microenvironment. When designing the functional synergist, the surface defect sites generated by the plasma excitation of the nano-silver sol form coordination binding with the peptide bond of lysozyme, enhancing its targeted hydrolysis ability to bacterial cell walls; the citrate in the absorbable buffer seamlessly connects with the tricarboxylic acid cycle metabolic pathway in the human body, actively mediating the absorption process through transmembrane transport proteins; at the same time, the cationic groups of chitosan quaternary ammonium salt activate the water in the mucus layer in the body fluid environment, accelerate the disintegration of the gel network into metabolizable fragments, and realize the synchronous degradation and removal of the coupling agent residues at the molecular level, thereby improving the safety and patient comfort of clinical operations.

[0060] By comparison and analysis of the related data in the table, it can be known that the absorbable disinfecting ultrasonic coupling agent prepared by the process has excellent disinfection efficiency, excellent sound conduction characteristics, rapid skin absorption and persistent adhesion stability. Therefore, it is shown that the product has advantages in avoiding cross infection, improving detection accuracy and optimizing patient experience, and is suitable for interventional ultrasound and transluminal ultrasound high requirement medical scenes, and has broad clinical application prospect and market promotion value.

[0061] It should be noted that, in this text, relational terms such as first and second are used merely to distinguish one entity or action from another, without necessarily requiring or implying any such actual relationship or order between such entities or actions. Moreover, the terms "comprises", "comprising", or any other variations thereof, are intended to cover non-exclusive inclusions, so that a process, method, article, or apparatus including a series of elements not only includes those elements, but also includes other elements not explicitly listed, or inherent to such a process, method, article, or apparatus. Without more limitations, the element defined by the statement "comprises a" does not exclude the presence of additional identical elements in the process, method, article, or apparatus including the element.

[0062] Although embodiments of the present application have been shown and described, it is to be understood that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the present application, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for preparing an absorbable and sterilizable ultrasonic coupling agent, characterized by: The method comprises the following steps: Step one: preparation of gelling base, selecting temperature-sensitive gel precursor, trehalose derivative and water-soluble polymer, mixing uniformly in a sterile environment; Step two: disinfection treatment, loading the disinfection active ingredient on mesoporous silica nanoparticles, and adding into the gelling base by ultrasonic dispersion; Step three: activation of functional synergist, plasma treatment of absorbable enhancement component; Step four: synthesis of coupling agent, mixing the gelling base after disinfection treatment and the activated functional synergist, gradient temperature reaction, and then cooling and filling; In step three, the functional synergist is made of the following raw materials by weight: 5-15 parts of nano-silver sol, 10-20 parts of chitosan quaternary ammonium salt, 3-8 parts of lysozyme, and 5-10 parts of absorbable buffer; In step two, the disinfection active ingredient is a compound of biguanide disinfectant and iodophor, and the mass ratio of biguanide disinfectant to iodophor is 1:0.5-1:

2.

2. The method for preparing an absorbable and disinfectable ultrasonic coupling agent according to claim 1, characterized in that: Step one comprises: The temperature-sensitive gel precursor is placed in a sterile reaction kettle, the temperature is controlled at 4-8℃, and the temperature-sensitive gel precursor is dissolved in water for injection by stirring at 200-500r / min, the trehalose derivative is continuously added, and then the water-soluble polymer is added after dissolution, and the stirring is maintained for 30-60min; The temperature-sensitive gel precursor is poloxamer 407, the trehalose derivative is trehalose laurate, and the water-soluble polymer is at least one of sodium hyaluronate or sodium carboxymethyl cellulose.

3. A method of preparing an absorbable and sterilizable ultrasonic coupling agent according to claim 2, characterized by: The mass ratio of poloxamer 407, trehalose laurate and water-soluble polymer is 15-25:5-10:1-3, the concentration of poloxamer 407 is 18-22wt%, and the degree of substitution of trehalose laurate is 0.8-1.

2.

4. The method for preparing an absorbable and disinfectable ultrasonic coupling agent according to claim 1, characterized in that: Step two comprises: The mesoporous silica nanoparticles are placed in a vacuum impregnation tank, vacuumed to 0.01-0.05kPa, and then the mixed solution of biguanide disinfectant and iodophor is injected, centrifuged after impregnation for 2-4h to obtain nanoparticles loaded with disinfection active ingredient, and the nanoparticles are added into the gelling base and ultrasonically dispersed at 20-40kHz for 15-30min under ice bath condition; The pore size of the mesoporous silica nanoparticles is 5-10nm, and the specific surface area is ≥800m² / g.

5. The method for preparing an absorbable and disinfectable ultrasonic coupling agent according to claim 1, characterized in that: Step three comprises: The nanometer silver sol, chitosan quaternary ammonium salt, lysozyme and absorbable buffer are placed in the plasma reaction cavity, vacuumed to 1x -1x Pa, argon is introduced to increase the pressure to 50-100 Pa, and treated for 5-15 min under the power of 200-400 W; The absorbable buffer is composed of sodium citrate and sodium bicarbonate at a mass ratio of 2:1, and the particle size of the functional synergist after plasma treatment is 80-150nm.

6. The method for preparing an absorbable and disinfectable ultrasonic coupling agent according to claim 1, characterized in that: Step four comprises: The functional synergist is added into the gelling base after disinfection treatment, and the mixture is stirred at 100-300r / min, the temperature is increased from 4℃ to 25℃ at a rate of 1℃ / min, and then increased to 37℃ at a rate of 0.5℃ / min, and the reaction is carried out at constant temperature for 1-2h, and then cooled to 4-8℃ for filling; The gradient temperature process is carried out in a self-foaming closed reactor, and the pressure in the reactor is maintained at 0.5-0.8MPa.

7. The preparation method of the absorbable disinfecting ultrasonic coupling agent according to claim 1, wherein: The final concentration of the absorbable buffer in the coupling agent is 0.1-0.5mol / L, and the pH value is adjusted to 6.8-7.

2. The mass ratio of the gel-forming base to the functional synergist is 8:1-5:

1.

8. An absorbable, sterilizable ultrasonic coupling agent, characterized by: The absorbable and sterilized ultrasonic coupling agent is prepared by the method of any one of claims 1-7, and the coupling agent comprises the following components by weight percentage: The temperature-sensitive gel base is 60-75%; The carrier of the sterilized active ingredient is 10-18%; The functional synergist is 15-25%; The viscosity of the coupling agent is 8000-15000 cP, the conductivity is ≤20 μS / cm, and the skin absorption rate at 37℃ is ≥95% / 30 min.

9. The absorbable and sterilized ultrasonic coupling agent according to claim 8, wherein: The biguanide disinfectant in the carrier of the sterilized active ingredient is polyhexamethylene biguanide hydrochloride, and the concentration is 0.2-0.8 wt%; the iodophor is polyvinylpyrrolidone iodine, and the effective iodine content is 0.05-0.2 wt%; The particle size of the nano-silver in the functional synergist is 10-30 nm, and the concentration is 50-100 ppm.

10. The absorbable and sterilized ultrasonic coupling agent according to claim 8, wherein: The coupling agent has storage stability of ≥ 12 months at 4-25℃, phase transition temperature of 33-35℃, ultrasonic attenuation coefficient of ≤ 0.5 dB / (cm·MHz), and acoustic impedance matching range of 1.4-1.6× Pa·s / m. The coupling agent has storage stability of ≥ 12 months at 4-25℃, phase transition temperature of 33-35℃, ultrasonic attenuation coefficient of ≤ 0.5 dB / (cm·MHz), and acoustic impedance matching range of 1.4-1.6× Pa·s / m.

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