Oxidation-resistant ultrasonic coupling agent and preparation method thereof

Abstract

The invention discloses an oxidation-resistant ultrasonic coupling agent and a preparation method thereof, and relates to the technical field of ultrasonic coupling agents. The ultrasonic coupling agent consists of the following components in parts by weight: 60-85 parts of a water-based matrix, 3-10 parts of a film-forming agent, 5-15 parts of a humectant, 0.5-5 parts of a thickening agent, 1-8 parts of an antioxidant compound and 0.1-1 part of a preservative. Through the synergistic effect of the deuterated site of the antioxidant compound and the active hydroxyl, the antioxidant stability of the system is remarkably improved, the free radical chain reaction is blocked, and oxidative deterioration is effectively delayed. Compared with a traditional product, the anti-oxidation long-life moisturizing gel has the remarkable advantages in the aspects of prolonging the anti-oxidation life, enhancing the moisturizing performance, improving the biological safety and controlling the attenuation of ultrasonic signals, and is suitable for long-term storage and high-precision ultrasonic diagnosis and treatment scenes.

Description

Technical Field

[0001] The present invention relates to the technical field of ultrasonic coupling agents, and in particular to an oxidation-resistant ultrasonic coupling agent and a preparation method thereof. Background Art

[0002] In the field of ultrasound diagnosis and treatment, ultrasonic coupling agent is a key intermediary substance. Its main function is to eliminate the air gap between the probe and the skin, so that ultrasound waves can be efficiently transmitted from the probe to human tissue, thereby ensuring the clarity of ultrasound imaging and diagnostic accuracy, and also facilitating the effective implementation of ultrasound treatment.

[0003] Although the common ultrasonic coupling agents currently on the market can meet the basic needs of acoustic conduction, there are also many problems that need to be solved. On the one hand, many traditional ultrasonic coupling agents have poor oxidative stability. During long-term use or storage, they are prone to performance degradation due to oxidation reactions, such as discoloration, deterioration, and poor acoustic conduction effects. This not only affects the quality of ultrasonic images, but may also shorten the service life of the coupling agent and increase medical costs. On the other hand, in order to ensure a certain service life, some coupling agents have added more preservatives, but this may cause adverse reactions such as skin allergies, especially for patients with more sensitive skin, there are certain safety hazards. In addition, the moisturizing properties of some coupling agents are not ideal, and they are easy to dry on the skin surface during use, which not only causes discomfort to patients, but may also affect the fit between the probe and the skin, thereby indirectly reducing the effect of ultrasonic testing.

[0004] Faced with these challenges, the industry is increasingly pressing for an ultrasonic coupling agent that combines excellent oxidation resistance, superior moisture retention, high safety, and stable performance. While various attempts have been made to improve existing technologies, they have yet to fully and effectively address these issues. Therefore, developing a new, oxidation-resistant ultrasonic coupling agent and its preparation method are of great practical significance for promoting the further application of ultrasound technology in the medical field. Summary of the Invention

[0005] The purpose of the present invention is to provide an oxidation-resistant ultrasonic coupling agent with good moisturizing properties and high safety, and a preparation method thereof, in order to address the problems of poor oxidation stability, easy deterioration, and possible skin allergies in existing ultrasonic coupling agents.

[0006] To achieve the above object, the technical solution adopted by the present invention is: an oxidation-resistant ultrasonic coupling agent, composed of the following components in parts by weight: 60-85 parts of an aqueous base, 3-10 parts of a film-forming agent, 5-15 parts of a humectant, 0.5-5 parts of a thickener, 1-8 parts of an antioxidant compound, and 0.1-1 parts of a preservative; The antioxidant compound is a compound represented by Formula 1: Formula 1; wherein D is deuterium; Z1 is selected from: O, S, N(R1), C(CH3)2, C(CD3)2; Z2 is selected from: O, S; R1 is selected from: H, deuterated methyl, deuterated tert-butyl, deuterated phenyl.

[0007] Furthermore, the aqueous matrix is selected from at least one of: aqueous glycerol solution, aqueous propylene glycol solution; In the aqueous glycerol solution, glycerol accounts for 10-30 wt%; in the aqueous propylene glycol solution, propylene glycol accounts for 5-15 wt%.

[0008] Furthermore, the film-forming agent is selected from at least one of: polyvinylpyrrolidone, sodium carboxymethylcellulose, sodium alginate.

[0009] Furthermore, the moisturizer is a compound mixture of polyol compounds and saccharide compounds, wherein: The polyol compounds are selected from at least one of: sorbitol, 1,3-propanediol, accounting for 80% of the total weight of the moisturizer; The saccharide compounds are selected from at least one of: sodium hyaluronate, mannitol, accounting for 20% of the total weight of the moisturizer.

[0010] Furthermore, the thickener is gum arabic or carbomer.

[0011] Furthermore, the preservative is selected from at least one of: sodium benzoate, potassium sorbate, benzalkonium bromide.

[0012] Furthermore, the antioxidant compound is any one of the compounds shown by the following structures:

[0013]

[0014]

[0015]

[0016] .

[0017] Furthermore, the synthesis steps of the antioxidant compound: ; The first step: Raw material 1 and raw material 2 undergo a substitution reaction to generate intermediate 1; The second step: Intermediate 1 undergoes borylation to generate intermediate 2; Step 2: Intermediate 2 and raw material 3 react via Suzuki-Miyaura reaction to generate antioxidant compounds.

[0018] A method for preparing an oxidation-resistant ultrasonic coupling agent comprises the following steps: S1. The aqueous matrix is heated to 40-60°C, the film-forming agent is added and stirred until completely dissolved to obtain a base liquid; S2. The base liquid is cooled to 25-30 ° C, and the moisturizing agent, thickener and antioxidant compound are sequentially added and dispersed at a stirring speed of 200-400 rpm for 20-40 minutes; S3. Add the preservative, continue stirring until transparent, then fill and sterilize to obtain an oxidation-resistant ultrasonic coupling agent.

[0019] Furthermore, when the antioxidant compound is added, the pH value of the system is controlled to be 6.5-7.5, and the pH value is adjusted using a phosphate buffer.

[0020] Furthermore, the sterilization is performed by moist heat sterilization at 121° C. for 20 min, followed by natural cooling to room temperature.

[0021] The multiple hydroxyl and deuterated sites in the antioxidant compound molecules described in the present invention can directly scavenge free radicals and block free radical chain oxidation reactions. The Z1 and Z2 groups protect the active groups through steric hindrance, thereby enhancing antioxidant stability. The active sites (-OH) in the molecules can simultaneously neutralize oxidative active substances to form a highly efficient antioxidant network. The bond energy of the carbon-deuterium bond is about 5-10 times higher than that of the carbon-hydrogen bond, which significantly reduces the reaction rate of free radicals capturing hydrogen atoms and prolongs the antioxidant life of the compound itself. Deuteration inhibits oxidative decomposition (such as dehydrogenation and hydroxylation reactions), reduces the generation of degradation products, and improves safety. In the moist environment of the ultrasonic coupling agent, the deuterated structure can withstand erosion by the water and oxygen environment and avoid side reactions with aqueous matrices (such as glycerol).

[0022] Traditional coupling agents are prone to generating free radicals due to ultrasonic cavitation, leading to oxidation and deterioration of the active ingredients. The antioxidant compounds described in this invention extend the antioxidant lifespan through high-density deuterated sites, directly capture free radicals, and block the oxidation chain reaction, which is the core guarantee for system stability. Conventional antioxidants (such as vitamin E) are easily diluted by the aqueous phase in coupling agents or deactivated by adsorption with film-forming agents (such as CMC-Na). However, the antioxidant compounds described in this invention achieve high dispersibility and long-lasting activity in aqueous matrices through their hydrophilic-hydrophobic amphiphilic structure.

[0023] The three-dimensional network formed by polyvinylpyrrolidone (PVP) or sodium alginate can immobilize antioxidant compounds, enabling their enrichment on the surface of the coupling agent and preferential contact with external oxygen free radicals. Polyols (such as sorbitol) bind to the hydroxyl groups of antioxidant compounds through hydrogen bonds, enhancing their solubility and the efficiency of intermolecular electron transfer, thereby improving the antioxidant efficiency. Preservatives such as benzalkonium bromide inhibit the growth of microorganisms, reduce the peroxides generated by microbial metabolism, indirectly reduce the oxidation pressure of the system, and form a "biological-chemical" double barrier with antioxidant compounds. The deuterated structure avoids proton exchange with the carboxylic acid groups of carbomer thickeners, maintains the pH stability of the system, and ensures that the functions of each component do not interfere with each other.

[0024] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. Significantly improve antioxidant stability: By introducing antioxidant compounds with deuterated structures, the free radical chain reaction is effectively blocked, the oxidation and deterioration process of the coupling agent is greatly delayed, and the storage and use cycle of the product is extended.

[0025] 2. Enhance long-term moisturizing performance: The synergistic compounding of polyols and saccharide compounds forms a dense moisturizing network, significantly improving the water-locking ability, maintaining skin moisture, and prolonging the probe adhesion time.

[0026] 3. Optimize biosecurity: The deuterated antioxidant compound system reduces the dosage of traditional preservatives, while inhibiting the generation of oxidation degradation products, reducing the risk of skin irritation and allergy.

[0027] 4. Improve acoustic conduction efficiency: The specific component ratio and the film-forming agent act synergistically to form a low-impedance dielectric layer, improving the ultrasonic conduction efficiency and reducing signal attenuation, ensuring imaging clarity. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 It is the synthesis route of the antioxidant compound described in the present invention.

[0029] Figure 2 It is the moisturizing property data graph of an oxidation-resistant ultrasonic coupling agent prepared in Examples 1-6 and Comparative Examples 1-3 of the present invention at 0h, 4h, 8h, 12h, 16h, 20h, and 24h. DETAILED DESCRIPTION OF THE INVENTION

[0030] The technical solutions of the present invention will be clearly and completely described below in conjunction with the accompanying drawings in the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts fall within the protection scope of the present invention.

[0031] Synthesis Example 1 Synthesis of Antioxidant Compound 1: ; Step 1: Under a nitrogen atmosphere, add 20 g of raw material 1, 150 g of dichloromethane, and 20.99 g of AlCl3 to the reaction system. After stirring evenly, slowly dropwise add 100 ml of a dichloromethane solution containing 17.05 g of raw material 2 (starting from -20 °C and the temperature not exceeding 0 °C during the dropping process), and react at room temperature until completion. Subsequently, lower the temperature of the reaction system to 0 °C, adjust the pH to neutral with 0.1 mol / L HCl, stir for 30 min, then let it stand for liquid separation, and retain the organic phase. Wash the aqueous phase with 50 ml of dichloromethane 2 - 3 times, combine the organic phases, dry with anhydrous magnesium sulfate, filter, and then rotary evaporate to obtain a solid. Purify it using a silica gel column with a mixed solution of petroleum ether / ethyl acetate as the eluent, concentrate and dry it, and finally obtain 28.95 g of intermediate 1. MS[MS + 1]: 397.

[0032] Step 2: Under a nitrogen atmosphere, add 28.95 g of intermediate 1 and 300 g of ultra-dry tetrahydrofuran to the reaction system, cool down to -70 °C, dropwise add 5.13 g of n-butyllithium. After the addition is complete, stir for 1 h, then dropwise add 16.45 g of triisopropyl borate. After the addition is complete, naturally raise the temperature to room temperature and react for 10 h. Rotary evaporate to remove the solvent to obtain 22.13 g of intermediate 2. MS[MS + 1]:

[0033] Step 3: Under a nitrogen atmosphere, add 22.13 g of intermediate 2, 33.22 g of raw material 3, 16.89 g of anhydrous potassium carbonate, and 2.12 g of tetrakis(triphenylphosphine)palladium to the reaction system, dissolve them in a mixed solution of 220 g of toluene, ethanol, and water (volume ratio 2:1:1), heat to reflux at 75 °C for 10 hours, turn off the heating, cool to room temperature, let it stand for liquid separation, extract the aqueous phase with ethyl acetate twice, combine the organic phases, wash with water three times, rotary dry, perform column chromatography with a mixed solution of petroleum ether and ethyl acetate as the eluent to obtain 35.82 g of antioxidant compound 1. MS[MS + 1]: 677.

[0034] of antioxidant compound 1 11H NMR (in deuterated chloroform) is as follows: δ 7.72 - 7.65 (m, 1H), 7.58 - 7.51 (m, 2H), 7.43 (tdd, 1H), 7.34 (td, 1H), 7.19 (s, 1H), 7.05 (dd, 1H), 6.92 (d, 1H), 5.78 (dd, 1H), 5.25 (dd, 1H), 5.17 - 5.09 (m, 1H), 5.11 - 5.02 (m, 1H), 4.98 (d, 1H), 4.54 - 4.45 (m, 2H), 4.21 (s, 1H), 3.70 (dd, 1H), 3.06 (dt, 1H), 2.80 (dt, 1H), 2.77 (s, 3H), 2.19 (dt, 1H), 1.98 - 1.89 (m, 1H), 1.25 (d, 6H), 1.18 (d, 6H).

[0035] Synthesis Example 2 - Synthesis Example 6 For the antioxidant compounds prepared in Synthesis Example 2 - Synthesis Example 6, referring to the synthesis method of Synthesis Example 1, replace Raw Material 1 and Raw Material 2 therein, and keep the rest the same as Synthesis Example 1. The specific structures of Raw Material 1, Raw Material 2, the antioxidant compound, and the MS [MS + 1] data are shown in the following table.

[0036]

[0037] Example 1 This example provides an oxidation - resistant ultrasonic coupling agent, which is composed of the following components in parts by weight: aqueous matrix: 75 parts (select an aqueous glycerol solution, where glycerol accounts for 20 wt% of the total weight of the aqueous solution); film - forming agent: 6 parts (polyvinylpyrrolidone); moisturizer: 10 parts (compounded from sorbitol and sodium hyaluronate in a weight ratio of 80:20); thickening agent: 2 parts (carbomer); antioxidant compound: 4 parts (using antioxidant compound 1 prepared in Synthesis Example 1); preservative: 0.5 part (sodium benzoate).

[0038] The preparation method includes the following steps: Heat the aqueous glycerol solution to 50 °C, add polyvinylpyrrolidone, and stir at a speed of 300 rpm until completely dissolved to obtain a transparent base liquid. Cool the base liquid to 25 °C, successively add sorbitol, sodium hyaluronate, carbomer, and antioxidant compound 1, adjust the pH of the system to 7.0 (using 0.1 M phosphate buffer solution), and stir and disperse at a speed of 350 rpm for 30 minutes. Add sodium benzoate, continue stirring until the system is homogeneous and transparent, fill it, and sterilize it at 121 °C by moist heat for 20 minutes, and then naturally cool to room temperature to obtain the oxidation - resistant ultrasonic coupling agent.

[0039] Example 2 - Example 6 An oxidation-resistant ultrasonic coupling agent prepared in Examples 2-6, referring to the preparation method of Example 1, sequentially replaces the antioxidant compound therein with the antioxidant compounds prepared in Synthesis Examples 2-6, and the rest is the same as in Example 1.

[0040] Comparative Example 1 An oxidation-resistant ultrasonic coupling agent, referring to the preparation method of Example 1, replaces the antioxidant compound therein with Comparative Compound 1, and the rest is the same as in Example 1.

[0041] Comparative Compound 1: 。

[0042] Comparative Example 2 An oxidation-resistant ultrasonic coupling agent, referring to the preparation method of Example 1, replaces the antioxidant compound therein with Comparative Compound 2, and the rest is the same as in Example 1.

[0043] Comparative Compound 2: 。

[0044] Comparative Example 3 An oxidation-resistant ultrasonic coupling agent, referring to the preparation method of Example 1, does not add the antioxidant compound therein, and the rest is the same as in Example 1.

[0045] Performance Test: 1. Determination of peroxide value (POV): Weigh 1.00 g of the sample (an oxidation-resistant ultrasonic coupling agent prepared in Examples 1-6, Comparative Examples 1-3), add 30 mL of glacial acetic acid-isooctane mixed solution (volume ratio 3:2), and shake until completely dissolved. Add 0.5 mL of saturated potassium iodide solution (KI, concentration 30% w / v), shake in the dark for 5 minutes to allow the peroxide to react with KI to generate free iodine (I2). Add 30 mL of deionized water, titrate with 0.01 mol / L sodium thiosulfate standard solution until pale yellow, add 1 mL of starch indicator (1% w / v), and continue titrating until the blue color disappears. Record the volume of sodium thiosulfate consumed V (mL); Calculation formula: ; Where V0 is the blank titration volume (mL); N is the concentration of sodium thiosulfate (mol / L); m is the sample mass (g).

[0046] 2. Determination of oxidation induction period (OIT): The sample (an oxidation-resistant ultrasonic coupling agent prepared in Examples 1-6, Comparative Examples 1-3) is sealed in a transparent glass bottle and stored in a constant temperature oven at 25°C in the dark. Take samples every 5 days to measure the POV until POV≥5 meq / kg, and record the total number of days.

[0047] 3. Moisture Retention Performance Test: 0.5 g of the sample (an oxidation-resistant ultrasonic couplant prepared in Examples 1-6 and Comparative Examples 1-3) was evenly coated on a polytetrafluoroethylene film (simulating skin) and placed in an environment of 25 °C and 40% humidity. Weighing was carried out at 0 h, 4 h, 8 h, 12 h, 16 h, 20 h, and 24 h respectively, and the moisture retention rate (%) = (mass at 24 h / mass at 0 h) × 100% was calculated. The data are shown in Figure 2 .

[0048] 4. Acoustic Performance Test: Using the pulse echo method, the frequency was set at 5 MHz and the temperature was 25 °C. An ultrasonic probe was used to measure the sound velocity (m / s) and sound attenuation coefficient (dB / cm / MHz) of the sample (an oxidation-resistant ultrasonic couplant prepared in Examples 1-6 and Comparative Examples 1-3). Deionized water was used as the reference (sound velocity 1482 m / s, attenuation coefficient 0.002 dB / cm / MHz).

[0049]

[0050] The example group was significantly superior to the comparative example group in terms of antioxidant stability, moisture retention performance, and acoustic conduction performance. With the specific structural design of the antioxidant compound, the examples showed a longer oxidation induction period and a lower initial oxidation value, while maintaining excellent moisture retention ability, higher sound velocity, and lower sound attenuation coefficient. In the comparative example group, especially the control group without antioxidant added, all performance indicators showed an obvious downward trend, verifying the key role of the antioxidant compound of the present invention in the comprehensive performance of the couplant.

[0051] Although the embodiments of the present invention have been shown and described, it will be understood by those of ordinary skill in the art that various changes, modifications, substitutions, and variations can be made to these embodiments without departing from the principles and spirit of the present invention. The scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. An oxidation-resistant ultrasonic coupling agent, characterized in that, It consists of the following components by weight parts: 60 - 85 parts of an aqueous matrix, 3 - 10 parts of a film-forming agent, 5 - 15 parts of a humectant, 0.5 - 5 parts of a thickening agent, 1 - 8 parts of an antioxidant compound, and 0.1 - 1 part of a preservative; The antioxidant compound is the compound shown in Formula 1: Formula 1; The D is deuterium; The Z1 is selected from: O, S, N(R1), C(CH3)2, C(CD3)2; The Z2 is selected from: O, S; The R1 is selected from: H, deuterated methyl, deuterated tert-butyl, deuterated phenyl.

2. The anti-oxidative ultrasonic coupling agent according to claim 1, characterized in that, The aqueous matrix is selected from at least one of: an aqueous glycerol solution, an aqueous propylene glycol solution; In the aqueous glycerol solution, the proportion of glycerol is 10 - 30 wt%; in the aqueous propylene glycol solution, the proportion of propylene glycol is 5 - 15 wt%.

3. The anti-oxidative ultrasonic coupling agent according to claim 1, characterized in that, The film-forming agent is selected from at least one of: polyvinylpyrrolidone, sodium carboxymethyl cellulose, sodium alginate.

4. The anti-oxidative ultrasonic coupling agent according to claim 1, wherein The humectant is a compound mixture of a polyol compound and a saccharide compound, wherein: The polyol compound is selected from at least one of: sorbitol, 1,3-propanediol, accounting for 80% of the total weight of the humectant; The saccharide compound is selected from at least one of: sodium hyaluronate, mannitol, accounting for 20% of the total weight of the humectant.

5. An oxidation-resistant ultrasonic coupling agent according to claim 1, characterized in that, The thickening agent is gum arabic or carbomer.

6. The anti-oxidative ultrasonic coupling agent according to claim 1, wherein, The preservative is selected from at least one of: sodium benzoate, potassium sorbate, benzalkonium bromide.

7. An oxidation-resistant ultrasonic coupling agent according to claim 1, characterized in that, The antioxidant compound is any one of the compounds shown in the following structure: ； ； ； ； 。 8. A preparation method of an oxidation-resistant ultrasonic coupling agent according to any one of claims 1-7, characterized in that, It includes the following steps: S1. Heat the aqueous matrix to 40 - 60 °C, add the film-forming agent and stir until completely dissolved to obtain a base liquid; S2. Cool the base liquid to 25 - 30 °C, sequentially add the humectant, thickening agent and antioxidant compound, and stir and disperse at a speed of 200 - 400 rpm for 20 - 40 minutes; S3. Add the preservative, continue to stir until transparent, then fill, sterilize to obtain an oxidation-resistant ultrasonic coupling agent.

9. The preparation method of an oxidation-resistant ultrasonic coupling agent according to claim 8, characterized in that, When adding the antioxidant compound, control the pH value of the system to be 6.5 - 7.5, and adjust the pH value with a phosphate buffer solution.

10. The preparation method of an oxidation-resistant ultrasonic coupling agent according to claim 8, characterized in that, The sterilization is by the moist heat sterilization method, sterilize at 121 °C for 20 min, and naturally cool to room temperature after sterilization.

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