Two-component contrast agents for gastric sonography and manufacturing processes thereof

Abstract

A two-component contrast agent for gastric sonography, characterized in that the contrast agent comprises two components, wherein component A contains functionalized silicon dioxide particles, an antifoaming agent, a preservative, sodium alginate, citric acid and water, and wherein component B is a calcium chloride solution.wherein the density of the functionalized silicon dioxide particles is the same as the liquid density of component A of the contrast agent; and wherein the functionalized silicon dioxide particles are biocompatible polymer-modified silicon dioxide particles with a mass percentage of 0.5-1.5% in component A; and wherein the particle size of the silicon dioxide in the biocompatible polymer-modified silicon dioxide particles is 70-90 mesh; and wherein the biocompatible polymer is one or more of polyethylene glycol, branched polyethylene glycol, chitosan, and hyaluronic acid; and wherein the biocompatible polymer is modified by grafting on an aldehyde group and an alcohol-soluble protein or by grafting on a sulfhydryl group and an alcohol-soluble protein.and wherein the aldehyde or sulfhydryl group is grafted onto 10-20% of the active group of the biocompatible polymer, and wherein the alcohol-soluble protein is grafted onto 5-10% of the active group of the biocompatible polymer; and wherein the polyethylene glycol and the branched polyethylene glycol have a hydroxyl group as the active group, and wherein the chitosan has an amino group as the active group and the hyaluronic acid has a carboxyl group as the active group; and wherein the mass percentage of sodium alginate in component A is 0.5-1%, and wherein the viscosity of the 1% aqueous solution thereof is 100-200 mP·s.and wherein the mass percentage of citric acid in component A is 4.2-6%; and wherein the calcium chloride solution in component B has a mass percentage concentration of 12.5-18%; and wherein the volume ratio between component A and component B of the contrast medium is 9:1; and wherein the mass ratio of citric acid to calcium chloride in the contrast medium is 3:1.

Description

TECHNICAL AREA The present invention relates to the technical field of medical ultrasound examination, in particular a contrast agent for gastric sonography and a manufacturing process thereof. STATE OF THE ART The stomach occupies three-quarters of the abdominal cavity volume and comprises the largest part of the digestive tract. It is the organ with the highest morbidity in the digestive system and also one of the organs with a high clinical morbidity rate. To clarify the location and nature of the lesion, various diagnostic procedures are frequently employed. These procedures include upper gastrointestinal barium feeding, gastroscopy, gastric CT scan, and MRI. Upper gastrointestinal barium feeding is simple, less painful, and generally well-tolerated by patients. However, the barium meal is radioactive, and the results are influenced by the barium coating, the filling effect, and the examiner's experience.Although barium sulfate is relatively safe, it can cause allergies, barium toxicity, barium leakage, and embedded barium sulfate fecal stones in a small number of patients. It can also worsen constipation and other adverse reactions and complications, and even lead to death, limiting its clinical use. Particularly in the elderly, patients with constipation, pregnant women, patients with barium allergy, patients with acute upper gastrointestinal bleeding, etc., the barium meal should not be used as a routine auxiliary diagnostic procedure. Gastroscopy can visualize the morphology and color of the gastric mucosa, the location, size, and depth of the lesion. It allows for direct visualization of the lesion and pathological examination to clarify its nature.However, gastroscopy can only clearly visualize the intraluminal structure; it cannot observe the layers of the stomach wall or the stomach's peristaltic movement. Since gastroscopy is an interventional procedure, most people experience discomfort, such as patients who cannot tolerate gastroscopy, elderly individuals with severe cardiopulmonary disease, patients in the acute stage of an upper gastrointestinal perforation, patients with acute severe throat diseases, patients in the acute stage of caustic esophageal injuries, and patients with mental disorders who are unable to cooperate, etc., which limits the application of gastroscopy both subjectively and objectively.Due to its high spatial resolution and clear anatomical structure, CT / MRI is a commonly used imaging method for staging gastric cancer, but it is not easy for CT / MRI to detect small lesions in the gastric cavity, and it has little diagnostic value for other diseases of the stomach and is not used as a routine examination method. Since the discovery of the piezoelectric effect and the inverse piezoelectric effect in physics at the beginning of the 20th century, ultrasound has rapidly opened a new chapter in the history of ultrasound technology. Due to its non-invasive, painless, cost-effective, well-tolerated, and non-radioactive nature, ultrasound has become a common and important examination method for the parenchymatous organs of the digestive system. Currently, three types of gastric ultrasound are used in clinical practice, including transabdominal gastric ultrasound, gastric filling ultrasound, and ultrasound endoscopy.Transabdominal ultrasound is intended only for preliminary screening; ultrasound endoscopy combines the advantages of endoscopy and ultrasound, compensates for their respective shortcomings, and further improves the diagnostic level of both, but due to its high cost, complex surgery, and potential trauma, it is limited to a few large hospitals and cannot be widely adopted; gastric filling ultrasound is a method in which the gastric cavity is filled with a contrast medium (also called an auxiliary wrapping agent) to eliminate interference from gastric gas and contents with the ultrasound waves, improve the internal environment of gastric sonography, and thus make the structure of the gastric wall and its lesions more clearly visible. This is the current trend in the development of sonography for gastric diseases and could be widely adopted.The contrast agent mainly comes in a non-echoic aqueous type and an echogenic powder type, and current application is mainly based on the echogenic powder type. Currently, contrast agents on the Chinese market are primarily manufactured using locally available traditional Chinese medicine or ingredients produced by grinding, mixing, and blending. For example, the contrast agents in CN102441180B and CN103611173B, which are formulated using Chinese medicine ingredients, have certain health-promoting and therapeutic effects. The contrast agent in CN1721000A is produced by grinding, mixing, and blending ingredients. It provides a better ultrasound imaging effect, but before use, it must be prepared by quickly stirring it with boiling water at 90-100°C to obtain a uniform paste solution. After cooling to a suitable temperature (generally 30-50°C), the patient is instructed to drink and ingest it or take it during the ultrasound examination. In addition to contrast agents based on Chinese medicine or ingredients, new contrast agent technologies are being developed that are easier to use and more effective. For example, the contrast agent described in patent CN107115534A uses a combination of osmotic pressure contrast agents, swelling agents, stabilizers, and defoamers to obtain a contrast agent with good tolerability and filling properties. In contrast, patent CN109745570A, in addition to using osmotic pressure contrast agents, adds a solid contrasting substance to improve the development effect and introduces bioactive substances such as bioactive glass, oligofructose, hyaluronic acid, etc., which offer certain health-promoting benefits. However, regardless of the type of contrast agent used, there are certain limitations. For example, the contrast agent used in Chinese medicine has a very good health-promoting effect, but its display interface under ultrasound is a low-echo interface, and the development effect is limited. Contrast agents of the ingredient type are complicated to use, and the waiting time is longer. Contrast agents to which a solid contrasting substance has been added require a suitable particle size of the solid contrasting substance, and the development effect is poor if the particles of the solid contrasting substance are too small or too large. If the particles of the solid contrasting substance are too small, the brightness of the developed surface is too low; if the particles of the solid contrasting substance are too large, the granulating property of the developed surface is too pronounced.Furthermore, the density of the solid contrasting substance should be matched to the liquid system of the contrast medium; a mismatched density affects product uniformity. If the density is too high, the solid contrasting substance will sink slightly in the liquid contrast medium; if the density is too low, the solid contrasting substance will float slightly in the liquid contrast medium.Finally, swelling agents must be added to the contrast medium to extend the window period, but if the contrast medium system has a high viscosity, it is difficult to expel the gas into the stomach, which easily leads to artifacts that affect the development effect. If the solid contrasting substance sinks or floats due to a density that is too high or too low, it is difficult to shake evenly. If the contrast medium system has a lower viscosity, the window period is too short, and the stomach quickly empties the contrast medium, causing problems for the clinician during gastric ultrasound diagnostics. CONTENT OF THE PRESENT INVENTION In view of the shortcomings of the aforementioned prior art, an objective of the present invention is to provide a two-component contrast agent for gastric sonography that has a stronger supportive effect on the gastric wall, is stable and uniform, and easily expels excess gas in the stomach during use and can also extend the window period. To achieve the above objective, the present invention employs the following technical solution: a two-component contrast agent for gastric sonography, comprising two components, a component A and a component B, wherein component A contains functionalized silicon dioxide particles, an antifoaming agent, a preservative, sodium alginate, citric acid, and water, and wherein component B is a calcium chloride solution. The density of the functionalized silicon dioxide particles is the same as the liquid density of component A of the contrast agent. The present invention utilizes the low viscosity of component A and the properties of the antifoaming agent it contains to fill the stomach while rapidly expelling gas and reducing interference from gas artifacts. Simultaneously, the functionalized silicon dioxide particles, along with gastric peristalsis, are rapidly dispersed on the gastric wall. Under the influence of aldehyde or sulfhydryl groups and alcohol-soluble proteins, they adhere to the lipoprotein layer of the gastric wall, forming a homogeneous and highly echogenic interface within the gastric wall, thereby increasing the rate of diagnosis and detection of diseases. Using component B increases the viscosity of the contrast medium, thus extending the window period and ensuring sufficient examination time. Furthermore, the functionalized silicon dioxide particles are biocompatible polymer-modified silicon dioxide particles with a mass percentage of 0.5-1.5% in component A. Furthermore, the particle size of the silicon dioxide in the biocompatible polymer-modified silicon dioxide particles is 70-90 mesh. Furthermore, the defoaming agent is at least one of an organosilicon defoaming agent and one of a polyether defoaming agent, wherein the organosilicon defoaming agent may be dimethicone or the like, and the polyether defoaming agent may be polyoxypropylene ethylene oxide glycerol ether or the like. The mass percentage of the defoaming agent in component A is 0.02–0.04%. Furthermore, the 1% aqueous solution of sodium alginate has a viscosity of 100-200 mPa·s, with the mass percentage of sodium alginate in component A being 0.5-1%. Furthermore, the mass percentage of citric acid in component A is 4.2-6%. Furthermore, the calcium chloride solution in component B has a mass percent concentration of 12.5-18%. Furthermore, the volume ratio between component A and component B of the contrast agent is 9:1, with component A and component B being packaged separately. Furthermore, the mass ratio of citric acid to calcium chloride in the contrast agent is 3:1. Furthermore, the preservative is sodium deoxyacetate, with the mass percentage of the preservative in component A being 0.03-0.05%. Furthermore, the biocompatible polymer is one or more of polyethylene glycol, branched polyethylene glycol, chitosan and hyaluronic acid. Furthermore, the biocompatible polymer is modified by grafting on an aldehyde group and an alcohol-soluble protein or by grafting on a sulfhydryl group and an alcohol-soluble protein. The aldehyde or sulfhydryl group is grafted onto 10-20% of the active group of the biocompatible polymer, while the alcohol-soluble protein is grafted onto 5-10% of the active group of the biocompatible polymer. Furthermore, polyethylene glycol and branched polyethylene glycol have a hydroxyl group as an active group, while chitosan has an amino group as an active group and hyaluronic acid has a carboxyl group as an active group. Furthermore, the viscosity of component A of the contrast agent is less than or equal to 100 mPa·s before mixing components A and B, and the viscosity of the contrast agent is greater than or equal to 500 mPa·s after sufficient mixing of components A and B. Furthermore, the procedure for the preparation of a two-component contrast agent for gastric sonography comprises the following steps: (1) Taking purified water, adding citric acid at 50-100 rpm, adjusting the speed to 800-1200 rpm after the citric acid has dissolved, adding sodium alginate in small amounts and several times, then adjusting the speed to 30-60 rpm, heating the solution to 90°C with continuous stirring, adjusting the speed to 50-100 rpm after the sodium alginate has completely dissolved, and then adding functionalized silicon dioxide particles, an antifoaming agent, and a preservative so that the functionalized silicon dioxide particles, the antifoaming agent, and the preservative are completely mixed with the solution to obtain component A. (2) Dissolving calcium chloride in purified water at 50-100 rpm to obtain the unsterilized component B.(3) Component A and the unsterilized component B are filled into polyester bottles; the unsterilized component B is sterilized by electron beam irradiation at 15-25 K to obtain component B. During the examination, component A is used first. This component has a low viscosity and can quickly expel gas as it fills the stomach, thus reducing interference from gas artifacts. Simultaneously, the functionalized silicon dioxide particles are rapidly dispersed on the stomach wall by gastric peristalsis. Under the influence of aldehyde or sulfhydryl groups and alcohol-soluble proteins, they adhere to the lipoprotein layer of the stomach wall, forming a homogeneous and highly echogenic interface. This increases the rate of diagnosis and disease detection. After component A has been used for 3 minutes, component B is used. Within 1 to 3 minutes, the viscosity of the contrast agent increases, extending the window period and ensuring sufficient examination time. The present invention has the following advantages: 1. The contrast agent mentioned in the present invention has a good developmental effect on the gastric wall. Through literature research, in vitro and in vivo validation, silicon dioxide particles with a specific particle size are selected and modified with biocompatible polymers grafted with specific functional groups. This increases the surface area of ​​the silicon dioxide particles through the use of biocompatible polymers and enhances the adhesion of the silicon dioxide particles to the lipoprotein layer of the gastric wall through the use of aldehyde or sulfhydryl groups and alcohol-soluble proteins. Accompanied by peristalsis in the stomach, the functionalized silicon dioxide particles can be rapidly dispersed and adhere to the gastric wall to form a homogeneous and highly echogenic interface, thus improving the diagnostic rate of the disease. 2.The contrast agent mentioned in the present invention does not cause the solid contrasting substance to float or sink, thus ensuring the uniformity and stability of the product. Due to the use of biocompatible polymer-modified silicon dioxide particles, whose density is the same as the liquid density of component A, the contrast agent does not sink or float during storage, thus ensuring the product's stability. 3. The contrast agent mentioned in the present invention ensures a sufficient window period and can expel excess gas in the stomach, thereby reducing the effects of gas artifacts on the imaging effect during gastric ultrasound examinations.The initial viscosity of component A is less than or equal to 100 mPa·s and it contains an antifoaming agent. Upon entering the stomach, it can quickly expel gas as it fills the stomach, thus reducing the interference of gas artifacts. After the use of component B, the degree of cross-linking of sodium alginate is increased under the action of citric acid and calcium ions, thereby increasing the viscosity of the contrast agent and extending the window period, which can ensure sufficient examination time. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 shows a viscosity diagram of a two-component contrast agent for gastric sonography and its component A at 37 ± 0.2°C. DETAILED DESCRIPTION The present invention is described in more detail below in connection with the exemplary embodiments, and it should be noted that the following description serves only to explain the present invention and does not limit its content. Unless otherwise specified, the particle size of the silicon dioxide in the biocompatible polymer-modified silicon dioxide particles used in the embodiments and comparative examples is 70-90 mesh. The volume ratio between component A and component B of the contrast agent is 9:1; the mass ratio of citric acid to calcium chloride in the contrast agent is 3:1. Example 1 A specific quantity of purified water is drawn, citric acid (the mass fraction of citric acid in component A is 5%) is added at 50-100 rpm, and the speed is allowed to dissolve. The speed is then set to 800-1200 rpm. Sodium alginate (the mass fraction of sodium alginate in component A is 0.7%) with a viscosity of 150 mP·s in a 1% aqueous solution is added in small amounts and repeatedly. The speed is then set to 30-60 rpm. The solution is heated to 90°C while stirring continuously. After the sodium alginate has completely dissolved, the speed is set to 50-100 rpm. Silicon dioxide particles functionalized with polyethylene glycol with a sulfhydryl grafting rate of 15% and an alcohol-soluble protein grafting rate of 7.5% (the mass fraction of silicon dioxide particles in component A is...) are then added. 1%), Dimethylsiloxane (the mass fraction of dimethylsiloxane in component A is 0,0.03%) and sodium deoxyacetate (the mass fraction of sodium deoxyacetate in component A is 0.04%) are added so that the functionalized silicon dioxide particles, the dimethylsiloxane, and the sodium deoxyacetate are completely mixed with the solution to obtain component A, in which the density of the functionalized silicon dioxide particles is the same as the liquid density of component A. Calcium chloride (the mass fraction of calcium chloride in component B is 15%) is dissolved at 50–100 rpm in purified water to obtain the unsterilized component B. Component A and the unsterilized component B are filled into polyester bottles; the unsterilized component B is sterilized by electron beam irradiation at 25 K to obtain component B. Example 2 A specific quantity of purified water is drawn, citric acid (the mass fraction of citric acid in component A is 4.2%) is added at 50-100 rpm, and the speed is allowed to dissolve. The speed is then set to 800-1200 rpm. Sodium alginate (the mass fraction of sodium alginate in component A is 0.5%) with a viscosity of 200 mP·s in a 1% aqueous solution is added in small amounts and repeatedly. The speed is then set to 30-60 rpm. The solution is heated to 90°C while stirring continuously. After the sodium alginate has completely dissolved, the speed is set to 50-100 rpm. Silicon dioxide particles functionalized with chitosan (with a 20% aldehyde graft and a 5% alcohol-soluble protein graft) are then added. 0.5%),Polyoxypropylene ethylene oxide glycerol ether (the mass fraction of polyoxypropylene ethylene oxide glycerol ether in component A is 0.02%) and sodium deoxyacetate (the mass fraction of sodium deoxyacetate in component A is 0.05%) are added so that the functionalized silicon dioxide particles, the polyoxypropylene ethylene oxide glycerol ether, and the sodium deoxyacetate are completely mixed with the solution to obtain component A, in which the density of the functionalized silicon dioxide particles is the same as the liquid density of component A. Calcium chloride (the mass fraction of calcium chloride in component B is 12.5%) is dissolved at 50–100 rpm in purified water to obtain the unsterilized component B. Component A and the unsterilized component B are filled into polyester bottles; the unsterilized component B is sterilized by electron beam irradiation at 25 K to obtain component B. Example 3 A specific quantity of purified water is drawn off, citric acid (the mass fraction of citric acid in component A is 6%) is added at 50-100 rpm, and the speed is allowed to dissolve. The speed is then set to 800-1200 rpm. Sodium alginate (the mass fraction of sodium alginate in component A is 1%) with a viscosity of 100 mP·s in a 1% aqueous solution is added in small amounts and repeatedly. The speed is then set to 30-60 rpm. The solution is heated to 90°C while stirring continuously. The speed is set to 50-100 rpm after the sodium alginate has completely dissolved. Then, silicon dioxide particles (the mass fraction of silicon dioxide particles in component A is 1.5%) functionalized with hyaluronic acid, a sulfhydryl graft of 10%, and a graft of 10% alcohol-soluble protein are added. Dimethylsiloxane (the mass fraction of dimethylsiloxane in component A is 0,0.04%) and sodium deoxyacetate (the mass fraction of sodium deoxyacetate in component A is 0.03%) are added so that the functionalized silicon dioxide particles, the dimethylsiloxane, and the sodium deoxyacetate are completely mixed with the solution to obtain component A, in which the density of the functionalized silicon dioxide particles is the same as the liquid density of component A. Calcium chloride (the mass fraction of calcium chloride in component B is 18%) is dissolved at 50–100 rpm in purified water to obtain the unsterilized component B. Component A and the unsterilized component B are filled into polyester bottles; the unsterilized component B is sterilized by electron beam irradiation at 15 K to obtain component B. Example 4 All others are the same as in embodiment 1, the difference being that the functionalized silicon dioxide particles are functionalized by polyethylene glycol with a sulfhydryl grafting rate of 10% and a grafting rate of the alcohol-soluble protein of 5%, wherein the mass fraction of this in component A is 0.5%, and wherein the density of the functionalized silicon dioxide particles is the same as the liquid density of component A. Example 5 All others are the same as in embodiment 1, the difference being that the functionalized silicon dioxide particles are silicon dioxide particles functionalized by polyethylene glycol with a sulfhydryl grafting rate of 20% and a grafting rate of the alcohol-soluble protein of 10%, wherein the mass fraction of this in component A is 1.5%, and wherein the density of the functionalized silicon dioxide particles is the same as the liquid density of component A. Example 6 All others are the same as in embodiment 1, the difference being that the mass fraction of sodium alginate in component A is 0.5%, and the viscosity of the 1% aqueous solution of sodium alginate is 200 mP·s. Example 7 All others are the same as in embodiment 1, the difference being that the mass fraction of sodium alginate in component A is 1%, and the viscosity of the 1% aqueous solution of sodium alginate is 100 mP·s. Example 8 All others are the same as in embodiment 1, the difference being that the mass fraction of sodium citrate in component A is 4.2%, and the mass fraction of calcium chloride in component B is 12.5%. Example 9 All others are the same as in embodiment 1, the difference being that the mass fraction of sodium citrate in component A is 6%, and the mass fraction of calcium chloride in component B is 18%. Comparative example 1 All others are the same as in embodiment 1, the difference being that the silicon dioxide particles are not modified for functionalization. Comparative example 2 All others are the same as in embodiment 1, the difference being that the silicon dioxide particles are modified with polyethylene glycol, while the polyethylene glycol is not grafted onto sulfhydryl groups and alcohol-soluble protein. Comparative example 3 All others are the same as in embodiment 1, the difference being that the silicon dioxide particles are modified with polyethylene glycol, wherein the polyethylene glycol has a sulfhydryl grafting rate of 5% and a grafting rate of the alcohol-soluble protein of 2.5%. Comparative example 4 All others are the same as in embodiment 1, the difference being that component A and component B are provided in a mixed state. Comparative example 5 All others are the same as in embodiment 1, the difference being that the mass fraction of sodium alginate in component A is 0.2%. Comparative example 6 All others are the same as in embodiment 1, the difference being that no defoaming agent is added. The biocompatible polymer-modified silicon dioxide particles can be produced using the methods described in the following literature: “Functionalization of nanomaterials from mesoporous silicon dioxide and investigations on drug entrainment and in vitro release” (Shuai Wang, Functionalization of nanomaterials from mesoporous silicon dioxide and investigations on drug entrainment and in vitro release [D]. Guizhou University, 2020).), “Mesoporous silicon dioxide nanoparticles doubly modified by sulfhydryl groups and carboxyl groups and their manufacturing process” (CN107055553A), “Production of mesoporous silicon dioxide nanoparticles modified by polyethylene glycol capped by carboxyl groups and their use” (CN108046276A), “Study of a drug delivery system based on mesoporous silicon dioxide” (Shi Shaoming, Study of a drug delivery system based on mesoporous silicon dioxide [D]. Changzhou University, 2021.), “Design of a controlled-release drug delivery system based on aminated mesoporous silicon dioxide / biomolecules” (Shangji Li, Design of a controlled-release drug delivery system based on aminated mesoporous silicon dioxide / biomolecules [D], Changzhou University, 2021.), “Activation of silicon dioxide nanoparticles by alginate derivatives for the production of Pickering emulsions” (Cheng Chunfeng, Jiacheng Li, Huiqiong Yan, Ruolin Liu, Chunxiu Wang, Qiang Lin, Activation of silicon dioxide nanoparticles by alginate derivatives for the production of Pickering emulsions [J], Daily Chemical Industry, 2014,44(05):241-246 .). In accordance with YY / T 0681.1-2018 Test Procedures for Packaging of Sterile Medical Devices - Part 1: Guidelines for Accelerated Aging Tests, the contrast medium for gastric sonography produced in Exemplary Works 1-9 and Comparative Examples 1-6 is subjected to accelerated aging at 60°C for 65 days with a target validity of 2 years, and the homogeneity of the samples after aging is recorded. The results are shown in Table 1 below. Table 1 Homogeneity of Samples after Accelerated Aging Example 1 homogeneous / Comparison example 1 non-homogeneous Solid particle settling Example of implementation 2 homogeneous / Comparison example 2 homogeneous / Example of implementation 3 homogeneous / Comparison example 3 homogeneous / Example 4 homogeneous / Comparison example 4 non-homogeneous: Solid particles float up Execution homogeneous / Comparison homogeneous / Example 5 Example of implementation 6 homogeneous / Comparison example 6 homogeneous / Example 7 homogeneous / Example 8 homogeneous / Example 9 homogeneous / Table 1 shows that in embodiments 1-9, comparative example 2, comparative example 3, comparative example 5, and comparative example 6, samples are uniform after accelerated aging, and there is no problem with solid particles floating or sinking. The silicon dioxide particles in comparative example 1 are not functionally modified, and their density is higher than the liquid density of component A, so the phenomenon of solid particles sinking occurs. In comparative example 4, component A and component B are stored in a mixed state, and although the samples initially exhibited more lasting homogeneity due to the high overall viscosity, the phenomenon of solid particles floating eventually occurs after complete aging. This is attributed to the low density of the functionalized silicon dioxide particles compared to the mixed solution. The viscosity of the contrast medium for gastric sonography after mixing the A-component and two-components of embodiments 1-9 and comparison examples 1-6 is measured at 37 ± 0.2°C, as shown in Fig. 1. As can be seen from Fig. 1, the viscosity of component A in embodiments 1-9, comparative examples 1-3 and comparative examples 5-6 at 37 ± 0.2°C is less than 100 mPa·s and the viscosity of the two-component mixture of embodiments 1-9, comparative examples 1-4 and comparative example 6 is greater than 500 mPa·s, comparative example 4 is itself a two-component mixture sample without viscosity data in connection with component A, the concentration of sodium alginate in comparative example 5 is too low, and the viscosity after the two-component mixture still cannot reach the requirement of greater than or equal to 500 mPa·s. The developmental effect of the contrast agent for gastric sonography prepared in embodiments 1-3 and comparative examples 1-6 is tested as follows: In addition to the sample described in comparative example 4, four bottles containing 450 ml of the component A sample and 50 ml of the component B sample are prepared for each group; four bottles with a two-component mixture of the sample described in comparative example 4 are sufficient. The test animals are four Beagle dogs, females 2 and males 2, 9-11 months old, weighing approximately 10 kg. With the exception of the sample group described in comparative example 4, the other groups receive 450 ml of component A by intragastric administration 15 minutes before the imaging examination and 50 ml of component B 3 minutes later. The gastric filling state is observed by ultrasound examination 3 minutes after administration of component B.The sample group described in comparative example 4 is given 500 ml directly, and the gastric filling state is observed 6 minutes after administration. The assessment considers gastric wall hierarchy and structure, gastric morphology, indication of peristalsis and emptying function, satisfaction with the window period, and elimination of the gas artifact effect. The assessment criteria are shown in Table 2 below, and higher scores indicate greater ability. Table 2: Assessment criteria for the effect Layers and structures: 0 points. The layers and structures of the stomach wall are completely unrecognizable. 2 points. The layers and structures of the stomach wall are recognizable, but difficult to distinguish. 4 points. To a certain extent, the layers and structures of the stomach wall are relatively difficult to distinguish. 6 points. To a certain extent, the layers and structures of the stomach wall can be distinguished. 8 points. The layers and structures of the stomach wall are relatively easy to distinguish. 10 points: The layers and structures of the stomach wall are perfectly distinguishable. Morphology 0 points: The layers and structures of the stomach wall are completely unrecognizable. 1 point. The morphology of all parts of the stomach is recognizable, but difficult to distinguish. 2 points. To a certain extent, all parts of the stomach are relatively difficult to distinguish. 3 points. To a certain extent, all parts of the stomach can be distinguished. 4 points. All parts of the stomach are relatively easy to distinguish. 5 points. All parts of the stomach are perfectly clear. differentiate Display of peristalsis and emptying function: 0 points. Peristalsis and emptying of the stomach are completely undetectable. 1 point. Peristalsis and the emptying function of the stomach are recognizable, but difficult to assess. 2 points. To a certain extent, peristalsis and the emptying function of the stomach are relatively difficult to assess. 3 points. To a certain extent, peristalsis and the emptying function of the stomach can be distinguished. 4 points. Peristalsis and the emptying function of the stomach are relatively easy to distinguish. 5 points. Peristalsis and the emptying function of the stomach are completely distinct. Satisfaction with the effective examination window time: 0 points. The time of the gastric window is completely insufficient for observation. 1 point: The time spent in the gastric window is not yet sufficient for observation. 2 points. The time of the gastric window is sufficient for the fastest possible observation up to a certain point. 3 points. The time allotted for the gastric window is just sufficient to meet the requirements for observation at normal speed. 4 points. The time spent in the gastric window is relatively sufficient for observation at normal speed. 5 points. The time of the gastric window is sufficient for observation at normal speed. Effect of gas artifact removal: 0 points. The gas artifacts cannot be removed at all. 1 point: The gas artifacts can be easily eliminated, but the gas artifacts still impair the ultrasound observation of the gastrointestinal region. 2 points: The gas artifacts can be moderately eliminated, but the effects of the gas artifacts on the ultrasound observation of the gastrointestinal region are limited. 3 points: The gas artifacts can be moderately eliminated; the gas artifacts no longer impair ultrasound observation. 4 points. The gas artifacts must be significantly eliminated. 5 points. The gas artifacts must be completely eliminated. The development effects of embodiments 1-3 and comparative examples 1-6 are listed in Table 3 below. Table 3 Development Effect Table 3 Development Effect Example 11055556 Example 210554.7555.95 Example 3105554.755.95 Comparative example 1423.25153.05 Comparative example 25.543.53.7554.35 Comparative example 364.253.75454.6 Comparison example 4655404 Comparison example 51055155.2 Comparison example 610554.2515.05 Table 3 shows that the average ratings of embodiments 1-3 are all above 5.5, and the various ratings indicate that the effects of sample development described in embodiments 1-3 are as follows: the layers and structures of the gastrointestinal wall, the morphology of the gastrointestinal parts, and the peristalsis and emptying function of the gastrointestinal tract can be fully and clearly distinguished; the gas artifacts can be almost completely eliminated;and there is a sufficient gastric window time for observing normal velocity. The average ratings of Comparative Examples 1-6 are 3.05, 4.35, 4.6, 4, 5.2 and 5.05 respectively, and are thus significantly lower than the ratings of Embodiments 1-3. From the various ratings, it is evident that the silicon dioxide particles of Comparative Example 1 are not functionalized, and after component A has entered the stomach, it is unable to form a specific adhesion with the gastric wall, so that after the addition of component B, it can only be suspended in the gastric cavity. Due to the low content of the silicon dioxide particles themselves, their ratings are better, with the exception of gas artifact removal, and the other ratings are all significantly lower than those of Embodiments 1-3.Although the silicon dioxide particles in Comparative Example 2 do not have a specific functional group modification compared to Comparative Example 1, they do have a biocompatible polymer modification, and their density is relatively close to that of the sample liquid. In addition to the elimination of gas artifacts, the remaining evaluations are improved. Compared to Comparative Example 2, the silicon dioxide particles in Comparative Example 3 are modified with a certain amount of specific functional groups, but compared to Exemplary Examples 1-3, the content of functional groups is low, so their evaluations lie between Comparative Example 2 and Exemplary Examples 1-3.Comparative Example 4 is a premixed two-component sample that has a high initial viscosity in the stomach and cannot displace gas. At the same time, the proportion of functionalized silicon dioxide particles adhering to the stomach wall is also low, so that the hierarchical structure of the stomach wall, the satisfaction with the effective examination window time, and the removal of gas artifacts are low compared to Exemplars 1-3. Comparative Example 5 has a low sodium alginate content; although it can displace gas in the stomach better and the functionalized silicon dioxide particles adhere well to the stomach wall, the final viscosity is low, so the effective examination window time cannot meet the requirements. Comparative Example 6 does not contain an antifoaming agent, so the effect on removing gas artifacts is low. The embodiments described above do not represent all embodiments, but only a subset. The detailed explanation of the embodiments of the present invention is not intended to limit the scope of protection of the present invention, but merely to present selected embodiments. All other embodiments that a person skilled in the art in this field could obtain from the embodiments in the present invention without any creative work should be considered to be covered by the scope of protection of the present invention.

Claims

Two-component contrast agent for gastric sonography, characterized in that the contrast agent comprises two components, wherein component A contains functionalized silicon dioxide particles, an antifoaming agent, a preservative, sodium alginate, citric acid and water, and wherein component B is a calcium chloride solution.wherein the density of the functionalized silicon dioxide particles is the same as the liquid density of component A of the contrast agent; and wherein the functionalized silicon dioxide particles are biocompatible polymer-modified silicon dioxide particles with a mass percentage of 0.5-1.5% in component A; and wherein the particle size of the silicon dioxide in the biocompatible polymer-modified silicon dioxide particles is 70-90 mesh; and wherein the biocompatible polymer is one or more of polyethylene glycol, branched polyethylene glycol, chitosan, and hyaluronic acid; and wherein the biocompatible polymer is modified by grafting on an aldehyde group and an alcohol-soluble protein or by grafting on a sulfhydryl group and an alcohol-soluble protein.and wherein the aldehyde or sulfhydryl group is grafted onto 10-20% of the active group of the biocompatible polymer, and wherein the alcohol-soluble protein is grafted onto 5-10% of the active group of the biocompatible polymer; and wherein the polyethylene glycol and the branched polyethylene glycol have a hydroxyl group as the active group, and wherein the chitosan has an amino group as the active group and the hyaluronic acid has a carboxyl group as the active group; and wherein the mass percentage of sodium alginate in component A is 0.5-1%, and wherein the viscosity of the 1% aqueous solution thereof is 100-200 mP·s.and wherein the mass percentage of citric acid in component A is 4.2-6%; and wherein the calcium chloride solution in component B has a mass percentage concentration of 12.5-18%; and wherein the volume ratio between component A and component B of the contrast medium is 9:1; and wherein the mass ratio of citric acid to calcium chloride in the contrast medium is 3:

1. Two-component contrast agent for gastric sonography according to claim 1, characterized in that the antifoaming agent is at least one of an organosilicon antifoaming agent and a polyether antifoaming agent; wherein the mass percentage of the antifoaming agent in component A is 0.02-0.04%. Two-component contrast agent for gastric sonography according to claim 2, characterized in that the silicon organophosphate defoamer is dimethicone and the polyether defoamer is polyoxypropylene ethylene oxide glycerol ether. Two-component contrast medium for gastric sonography according to claim 1, characterized in that the preservative is sodium deoxyacetate, wherein its mass percentage in component A is 0.03-0.05%. Two-component contrast medium for gastric sonography according to one of claims 1 to 4, characterized in that the viscosity of component A of the contrast medium is less than or equal to 100 mPa·s before mixing components A and B, wherein the viscosity of the contrast medium is greater than or equal to 500 mPa·s after sufficient mixing of components A and B. A method for producing a two-component contrast agent for gastric sonography according to any one of claims 1 to 5, characterized in that it comprises the following steps: extraction of purified water, addition of citric acid at 50-100 rpm, setting the speed to 800-1200 rpm after the citric acid has dissolved, addition of sodium alginate in small amounts and several times, then setting the speed to 30-60 rpm, heating the solution to 90°C with continuous stirring, setting the speed to 50-100 rpm after the sodium alginate has completely dissolved, and then adding functionalized silicon dioxide particles, an antifoaming agent, and a preservative, such that the functionalized silicon dioxide particles, the antifoaming agent, and the preservative are completely mixed with the solution to obtain component A;Dissolving calcium chloride at 50-100 rpm in purified water to obtain the unsterilized component B; component A and the unsterilized component B are filled into polyester bottles; the unsterilized component B is sterilized by electron beam irradiation at 15-25 K to obtain component B.

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