Contrast agents for gastrointestinal sonography and manufacturing processes thereof

Abstract

A contrast agent for gastrointestinal sonography, characterized in that it consists of the following components in the following weight proportions: 2-4 parts of a thickening agent, 2-4 parts of an osmolality regulator, 1.5-2.5 parts of a solid contrasting substance, 0.02-0.04 parts of an antifoaming agent, 0.03-0.05 parts of a taste correction agent, 0.03-0.05 parts of a preservative, 89.36-94.42 parts of purified water; wherein the solid contrasting substance has the same density as the liquid density of the contrast agent; and wherein the thickening agent is one or more of Poroxam 407, Poroxam 338, Poroxam 237 and Poroxam 188; and wherein the solid contrasting substance is biocompatible polymer-modified silicon dioxide particles; and wherein the biocompatible polymer is one or more of polyethylene glycol, branched polyethylene glycol, chitosan, alginate, hyaluronic acid and polysiloxane;and wherein the silicon dioxide particles are a mixture of silicon dioxide particles of different particle sizes in a specific ratio; and wherein the specific formula is: silicon dioxide particles of particle sizes 75-85 mesh, 85-95 mesh, 95-105 mesh and 105-120 mesh are mixed in the mass ratio of (60-65) :(15-20):(5-10):(5-20) to be homogeneously mixed; and wherein the preservative is sodium deoxyacetate.;

Description

TECHNICAL FIELD

[0001] The present invention relates to the technical field of medical ultrasound examination, in particular to a developing agent for gastrointestinal sonography and a manufacturing method thereof. STATE OF THE ART

[0002] The gastrointestinal tract occupies three-quarters of the volume of the abdominal cavity and constitutes the largest part of the alimentary canal. 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 examination techniques are often used to assist in the diagnosis. Examination techniques of the gastrointestinal tract include an upper barium meal, gastroscopy, gastric enteral CT, and MRI. An upper barium meal is simple, less painful, and easily accepted by patients. However, the barium meal is radioactive, and the results are affected by the barium coating, the filling effect, and the experience of the examiner.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, aggravate constipation and other adverse reactions and complications, and even lead to death, which limits its clinical application, especially in the elderly, patients with constipation, pregnant women, patients with barium allergy, and patients with acute upper digestive tract bleeding, barium meal cannot be used as a routine auxiliary diagnostic method. Gastroscopy can visualize the morphology and color of the gastric mucosa, the location of the lesion, the size of the lesion, and the depth of the lesion. It can also see the lesion under direct vision and perform pathological examination to clarify the nature of the lesion.However, gastroscopy can only clearly demonstrate the intraluminal structure, and it cannot observe the layers of the gastric wall and the peristaltic movement of the stomach. Because gastroscopy is an interventional examination, most people have discomfort, such as patients who cannot tolerate gastroscopy, the elderly with severe cardiopulmonary diseases, patients in the acute stage of upper digestive tract perforation, patients with acute severe pharyngeal diseases, patients in the acute stage of caustic esophageal injury, and patients with mental disorders who cannot cooperate with the patient, 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 has little diagnostic value for other gastrointestinal diseases and is not used as a routine examination method.

[0003] 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 parenchymal organs of the digestive system.

[0004] Currently, three types of gastrointestinal ultrasound examination are used in clinical practice, including transabdominal gastrointestinal ultrasound examination, gastrointestinal filling ultrasound examination, and ultrasound endoscopy. Transabdominal gastrointestinal ultrasound examination is only for preliminary screening; ultrasound endoscopy combines the advantages of endoscopy and ultrasound examination, compensates for their respective shortcomings, and further improves the diagnostic level of endoscopy and ultrasound examination. However, due to its high price, complex operation, and certain trauma, it is limited to a few large hospitals and cannot be widely used.Gastrointestinal filling ultrasound is a method in which the gastrointestinal cavity is filled with a contrast agent (also called a developing agent) to eliminate the interference of gas and contents in the gastrointestinal cavity with ultrasound waves, improve the internal environment of gastrointestinal sonography, and thus make the structure of the gastrointestinal wall and its lesions more clearly visible. This is the development trend of ultrasonography for gastrointestinal diseases and can be widely used. The contrast agent mainly has a non-echoic aqueous type and an echogenic powder type, and the current application is mainly based on the echogenic powder type.

[0005] Currently, contrast agents on the Chinese market are mainly made using locally available traditional Chinese medicine or ingredients by grinding, mixing, and blending. For example, the developing agents in CN102441180B, CN103611173B, etc., which are made from Chinese medicine formulations, have certain health care effects and therapeutic effects. The developing agent in CN1721000A is made by grinding, mixing, and blending ingredients. The ultrasound imaging effect is better, but before use, it must be directly brewed with boiling water at 90-100°C and stirred quickly to obtain a uniform paste solution. After cooling to an appropriate temperature (generally 30-50°C), the patient is advised to drink it before performing the ultrasound examination or to drink it during the ultrasound examination.

[0006] In addition to developing agents based on Chinese medicine or ingredients, developing agent technologies are being developed that are easier to use and more effective. For example, the developing agent described in patent CN107115534A uses a combination of osmotic pressure contrast agents, swelling agents, stabilizers, and defoamers to obtain a developing agent with good compatibility and good filling effect. In contrast, patent CN109745570A, in addition to the use of osmotic pressure contrast agents, adds a solid contrast agent to enhance the developing effect and introduces bioactive substances such as biologically active glass, oligofructose, hyaluronic acid, etc., which play a certain health-care function.

[0007] However, no matter what type of contrast agent is used, there are certain limitations. For example, the Chinese medicine contrast agent has very good health care effects, but its display interface under ultrasound is a low-echo interface, and the development effect is limited. The type of contrast agent is complicated to use, and the waiting time is longer.the developing agent in which a solid contrasting substance is added first needs a suitable size of the particles of the solid contrasting substance, and the developing 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 developing surface is too low, if the particles of the solid contrasting substance are too large, the granulating property of the developing surface is too strong;In addition, the density of the solid contrasting substance should be matched with the liquid system of the developing agent. A mismatch in density will affect the product uniformity. If the density is too high, the solid contrasting substance will easily sink in the liquid developing agent. If the density is too low, the solid contrasting substance will easily float in the liquid developing agent.Finally, swelling agents must be added to the developing agent to extend the window period. However, if the developing agent system has a high viscosity, it is difficult to expel the gas in the stomach and intestines, which easily leads to artifacts that affect the developing effect. If the solid contrast substance sinks or floats due to too high or too low density, it is difficult to shake evenly. If the developing agent system has a lower viscosity, the window period is too short, and the stomach and intestines quickly empty the developing agent, which brings interference to the clinician's gastrointestinal ultrasound diagnostic work. CONTENT OF THE PRESENT INVENTION

[0008] In view of the deficiencies of the above-mentioned prior art, an object of the present invention is to provide a developing agent for gastrointestinal ultrasonography which has a stronger developing effect, is stable and uniform, and easily expels excess gas in the stomach and intestines upon use, and can also prolong the window period.

[0009] To achieve the above objective, the present invention uses the following technical solution: A developing agent for gastrointestinal sonography, consisting of the following components in the following parts by weight: 2-4 parts of a thickener, 2-4 parts of an osmolality regulator, 1.5-2.5 parts of a solid contrasting substance, 0.02-0.04 parts of a defoamer, 0.03-0.05 parts of a taste corrector, 0.03-0.05 parts of a preservative, 89.36-94.42 parts of purified water; wherein the solid contrasting substance has the same density as the liquid density of the developing agent, and wherein the density is 1.028 g / ml-1.089 g / ml.

[0010] Furthermore, the thickener is one or more of Poroxam 407, Poroxam 338, Poroxam 237 and Poroxam 188.

[0011] Furthermore, the osmolality regulator is at least one of xylitol, mannitol.

[0012] Furthermore, the solid contrast substance comprises biocompatible polymer-modified silica particles; wherein the biocompatible polymer is one or more of polyethylene glycol, branched polyethylene glycol, chitosan, alginate, hyaluronic acid, and polysiloxane.

[0013] Furthermore, the biocompatible polymer modifies the silica particles by one or more of sol-gel process, one-step post-grafting process, two-step post-grafting process, and selective post-grafting process.

[0014] Furthermore, the silica particles are a mixture of silica particles of different particle sizes in a specific ratio; the specific formula is: silica particles of particle sizes of 75-85 mesh (excluding 85 mesh), 85-95 mesh (excluding 95 mesh), 95-105 mesh (excluding 105 mesh), and 105-120 mesh (excluding 120 mesh) are mixed in the mass ratio of (60-65):(15-20):(5-10):(5-20) to be mixed homogeneously.

[0015] Further, the defoamer is at least one of an organosilicon defoamer and a polyether defoamer, wherein the organosilicon defoamer may be dimethylsiloxane and the like, and the polyether defoamer may be polyoxypropylene-ethylene oxide-glycerol ether and the like.

[0016] Furthermore, the flavor corrector is one or more of strawberry flavor, lemon flavor and apple flavor.

[0017] Furthermore, the preservative is sodium deoxyacetate.

[0018] Furthermore, the gelling temperature of the developing agent is 20-30°C, with the viscosity of the developing agent being lower at temperatures below the gelling temperature and the viscosity of the developing agent increasing at temperatures above the gelling temperature.

[0019] Furthermore, the viscosity of the developing agent is less than or equal to 100 mPa s at 20±0.2°C and greater than or equal to 500 mPa s at 37°C±0.2°C.

[0020] In the present invention, a certain proportion of silica particles of different particle sizes is used to optimize the developing effect and ensure that the developing agent exhibits good developing effect in the ultrasound imaging interface; using biocompatible polymers, the silica particles are modified so that their density is the same as the liquid density of the developing agent, and in the storage process, the silica particles do not sink to ensure the stability of the product; a temperature-sensitive thickener is selected, the temperature-sensitive thickener has a high viscosity at normal temperature and a high viscosity at 37°C.At the beginning of the developing agent's arrival in the gastrointestinal tract, the overall temperature is low, and the low-viscosity state promotes the discharge of gases in the gastrointestinal tract, reducing the artifacts caused by residual gases; at a certain time after the developing agent reaches the gastrointestinal tract, the overall temperature rises to body temperature and the viscosity increases, thereby extending the window period for gastrointestinal examination and ensuring sufficient examination time.Furthermore, the method for preparing a developing agent for gastrointestinal sonography comprises the following steps: taking purified water, controlling its temperature at 2-4°C, slowly adding a thickener, a defoaming agent, a flavor corrector, and a preservative in sequence at 800-1200 rpm, and then adjusting the speed to 50-100 rpm, slowly adding a solid contrast agent, and then adjusting the speed to 800-1200 rpm, adding an osmolality regulator, stirring for 20-40 min, and finally filling it into a 500 mL brown polyester bottle to obtain a developing agent for gastrointestinal sonography.

[0021] The present invention has the following advantages: 1. The developing agent of the present invention has a good developing effect; through a variety of in vitro and ex vivo experiments, it is verified that a certain proportion of silica particles of different particle sizes is used to optimize the developing effect and ensure that the developing agent exhibits a good developing effect in the ultrasound imaging interface. 2. The developing agent of the present invention does not cause the solid contrasting substance to float or sink, thus ensuring the uniformity and stability of the product; using biocompatible polymers, the silica particles are modified so that their density is the same as the liquid density of the developing agent, and in the storage process, the silica particles do not sink or float, ensuring the stability of the product.3. The developing agent of the present invention ensures a sufficient window period and can expel excess gas in the gastrointestinal region and reduce the impact of gas artifacts on the developing effect for gastrointestinal ultrasound examination; a temperature-sensitive thickener is selected, the temperature-sensitive thickener has a high viscosity at normal temperature and a high viscosity at 37°C.At the beginning of the developing agent's arrival in the gastrointestinal tract, the overall temperature is low, and the low-viscosity state promotes the discharge of gases in the gastrointestinal tract, reducing the artifacts caused by residual gases; at a certain time after the developing agent reaches the gastrointestinal tract, the overall temperature rises to body temperature and the viscosity increases, thereby extending the window period for gastrointestinal examination and ensuring sufficient examination time. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 shows a graph of the viscosity of the developing agents for gastrointestinal sonography prepared in the respective embodiments of the present invention and the comparative examples at a temperature of 20°C±0.2°C. Fig.Fig. 2 shows a graph of the viscosity of the developing agents for gastrointestinal sonography prepared in the respective embodiments of the present invention and the comparative examples at a temperature of 37°C±0.2°C. DETAILED DESCRIPTION

[0022] The present invention will be described in more detail below in conjunction with the embodiments, and it should be noted that the following description only serves to explain the present invention and does not limit its content

[0023] Poroxam 407, Poroxam 338, Poroxam 237 and Poroxam 188 used in the working examples and comparative examples are commercially available products. Example 1

[0024] Take 91.84 g of purified water, control its temperature at 2-4°C, slowly add 2.7 g of Poroxam 338, 0.35 g of Poroxam 188, 0.03 g of dimethylsiloxane, 0.04 g of lemon flavor, 0.04 g of sodium deoxyacetate in sequence at 800-1200 rpm, then adjust the speed to 50-100 rpm, slowly add 2 g of polyethylene glycol modified silica particles with a density of 1.06 g / ml, the silica particles being according to the mass ratio of 75-85 mesh (excluding 85 mesh), 85-95 mesh (excluding 95 mesh), 95-105 mesh (excluding 105 mesh), 105-120 mesh (excluding 120 mesh) as 62.5:17.5:7.5:12.5 are mixed homogeneously, and then adjust the speed to 800-1200 rpm, add 3 g of xylitol, mix for 20-40 min and finally fill into a brown polyester bottle to obtain a developing agent for gastrointestinal sonography. Example 2

[0025] Taking 89.41 g of purified water, controlling its temperature at 2-4°C, slowly adding 3.7 g of Poroxam 407, 0.25 g of Poroxam 188, 0.04 g of polyoxypropylene ethylene oxide glycerol ether, 0.05 g of strawberry flavor, 0.05 g of sodium deoxyacetate in sequence at 800-1200 rpm, then adjusting the speed to 50-100 rpm, slowly adding 2.5 g of chitosan-modified silica particles with a density of 1.089 g / ml, wherein the silica particles are divided according to the mass ratio of 75-85 mesh (excluding 85 mesh), 85-95 mesh (excluding 95 mesh), 95-105 mesh (excluding 105 mesh), 105-120 mesh (excluding 120 mesh) as 60:15:5:20 are mixed homogeneously, and then adjust the speed to 800-1200 rpm, add 4 g of mannitol, mix for 20-40 min and finally fill into a brown polyester bottle to obtain a developing agent for gastrointestinal sonography. Example 3

[0026] Take 94.42 g of purified water, control its temperature at 2-4°C, slowly add 2 g of Poloxamer 407, 0.02 g of dimethylsiloxane, 0.03 g of apple flavor, 0.03 g of sodium deoxyacetate in sequence at 800-1200 rpm, then adjust the speed to 50-100 rpm, slowly add 1.5 g of alginate-modified silica particles with a density of 1.028 g / ml, the silica particles are homogeneously mixed according to the mass ratio of 75-85 mesh (excluding 85 mesh), 85-95 mesh (excluding 95 mesh), 95-105 mesh (excluding 105 mesh), 105-120 mesh (excluding 120 mesh) as 65:20:10:5, and then adjust the speed to 800-1200 rpm, adding 2 g of xylitol, mixing for 20-40 min and finally filling into a brown polyester bottle to obtain a developing agent for gastrointestinal sonography. Example 4

[0027] Take 93.39 g of purified water, control its temperature at 2-4°C, slowly add 2.5 g of Poroxam 338, 0.5 g of Poroxam 237, 0.03 g of dimethylsiloxane, 0.04 g of lemon flavor, 0.04 g of sodium deoxyacetate in sequence at 800-1200 rpm, then adjust the speed to 50-100 rpm, slowly add 1.5 g of hyaluronic acid modified silica particles with a density of 1.044 g / ml, the silica particles being according to the mass ratio of 75-85 mesh (excluding 85 mesh), 85-95 mesh (excluding 95 mesh), 95-105 mesh (excluding 105 mesh), 105-120 mesh (excluding 120 mesh) as 62.5:17.5:7.5:12.5 are mixed homogeneously, and then adjust the speed to 800-1200 rpm, add 2 g of xylitol, mix for 20-40 min and finally fill into a brown polyester bottle to obtain a developing agent for gastrointestinal sonography. Example 5

[0028] Take 90.39 g of purified water, control its temperature at 2-4°C, slowly add 2.9 g of Poroxam 407, 0.1 g of Poroxam 237, 0.03 g of dimethylsiloxane, 0.04 g of lemon flavor, 0.04 g of sodium deoxyacetate in sequence at 800-1200 rpm, then adjust the speed to 50-100 rpm, slowly add 2.5 g of polysiloxane-modified silica particles with a density of 1.078 g / ml, the silica particles being according to the mass ratio of 75-85 mesh (excluding 85 mesh), 85-95 mesh (excluding 95 mesh), 95-105 mesh (excluding 105 mesh), 105-120 mesh (excluding 120 mesh) as 62.5:17.5:7.5:12.5 are mixed homogeneously, and then adjust the speed to 800-1200 rpm, add 4 g of xylitol, mix for 20-40 min and finally fill into a brown polyester bottle to obtain a developing agent for gastrointestinal sonography. Example 6

[0029] Take 91.85 g of purified water, control its temperature at 2-4°C, slowly add 2.7 g of Poroxam 407, 0.35 g of Poroxam 188, 0.02 g of dimethylsiloxane, 0.03 g of lemon flavor, 0.05 g of sodium deoxyacetate in sequence at 800-1200 rpm, then adjust the speed to 50-100 rpm, slowly add 2 g of branched polyethylene glycol modified silica particles with a density of 1.061 g / ml, the silica particles being according to the mass ratio of 75-85 mesh (excluding 85 mesh), 85-95 mesh (excluding 95 mesh), 95-105 mesh (excluding 105 mesh), 105-120 mesh (excluding 120 mesh) as 62.5:17.5:7.5:12.5 are mixed homogeneously, and then adjust the speed to 800-1200 rpm, add 3 g of xylitol, mix for 20-40 min and finally fill into a brown polyester bottle to obtain a developing agent for gastrointestinal sonography. Comparison example 1

[0030] The steps are the same as in Example 1, the difference being that the thickener is 1.35 g of sodium carboxymethylcellulose, 1.35 g of hydroxypropylcellulose and 0.35 g of sodium hyaluronate. Comparison example 2

[0031] The steps are the same as in Example 1, the difference being that the thickener is 0.7 g Poroxam 338 and 0.15 g Poroxam 188. Comparison example 3

[0032] The steps are the same as in Example 1, the difference being that the thickener is 4.7 g of Poroxam 338 and 0.65 g of Poroxam 188. Comparison example 4

[0033] The steps correspond to those of Example 1, the difference being that the silicon dioxide particles of the solid contrasting substance are not modified with biocompatible polymers. Comparison example 5

[0034] The steps are the same as in Example 1, except that the silica particles of the solid contrasting substance all have a particle size of 75-85 mesh. Comparison example 6

[0035] The steps are the same as in Example 1, except that the silica particles of the solid contrasting substance all have a particle size of 105-120 mesh.

[0036] The biocompatible polymer-modified silica particles can be prepared using the methods described in the following literature: "Functionalization of mesoporous silica nanomaterials and studies on drug entrainment and in vitro release" (Shuai Wang, Functionalization of mesoporous silica nanomaterials and studies on drug entrainment and in vitro release [D]. Guizhou University, 2020.), "Mesoporous silica nanoparticles doubly modified by sulfhydryl groups and carboxyl groups and their preparation method" (CN107055553A), "Preparation of mesoporous silica nanoparticles modified by carboxyl groups capped polyethylene glycol and their use" (CN108046276A), "Study on a drug-carrying system based on mesoporous silica" (Shi Shaoming, Study on a drug-carrying system based on mesoporous silica [D]. Changzhou University, 2021.), "Construction of a controlled-release drug delivery system based on aminated mesoporous silica biomolecules" (Shangji Li, Construction of a controlled-release drug delivery system based on aminated mesoporous silica biomolecules [D], Changzhou University, 2021.), “Activation of silica nanoparticles by alginate derivatives for the preparation of Pickering emulsions” (Cheng Chunfeng, Jiacheng Li, Huiqiong Yan, Ruolin Liu, Chunxiu Wang, Qiang Lin, Activation of silica nanoparticles by alginate derivatives for the preparation of Pickering emulsions [J], Daily Chemical Industry, 2014,44(05):241-246.). “Preparation of functionalized mesoporous silica-loaded cisplatin nanomedicines and their killing effect on breast cancer cells” (Weikun Liu, Meng Zhang, Binglong Li, Xidong Guan, Mingshuang Sun, Yujing He, Chunxiao Wang, Baochang Zhao, Jimei Zhang, Preparation of functionalized mesoporous silica-loaded cisplatin nanomedicines and their killing effect on breast cancer cells [J], Academic Journal of Taishan Medical University, 2019, 40(11):801-805.).

[0037] According to YY / T 0681.1-2018, Test Methods for Sterile Medical Device Packaging - Part 1: Guidelines for Accelerated Aging Tests, the gastrointestinal sonography developer prepared in Working Examples 1-6 and Comparative Examples 1-6 was subjected to accelerated aging at 60°C for 65 days with a target validity of 2 years. The homogeneity of the samples after aging was recorded. The results are shown in Table 1 below. Table 1 Homogeneity of samples after accelerated aging grouping Sample homogeneity after accelerated aging Remarks grouping Sample homogeneity after accelerated aging Remarks Example 1 evenly / Comparison example 1 evenly / Example 2 evenly / Comparison example 2 uneven Solid particles sink Example 3 evenly / Comparison example 3 uneven Solid particles float on Example 4 evenly / Comparison example 4 uneven Solid particles sink Example 5 evenly / Comparison example 5 evenly / Example 6 evenly / Comparison example 6 evenly /

[0038] From Table 1, it can be seen that in Working Examples 1-6, Comparative Example 1, Comparative Example 5, and Comparative Example 6, the samples after accelerated aging are uniform, and there is no problem with the floating or sinking of solid particles. The density of the polyethylene glycol-modified silica particles in Comparative Example 2 and the silica particles not modified with biocompatible polymers in Comparative Example 4 is greater than the liquid density of the respective samples, so the solid particles sink, demonstrating the phenomenon of irregularity of the samples. The density of the polyethylene glycol-modified silica particles in Comparative Example 3 is lower than the liquid density of the respective samples, so the solid particles float, demonstrating the phenomenon of irregularity of the samples.

[0039] The viscosity of the developing agents for gastrointestinal sonography prepared in Working Examples 1-6 and Comparative Examples 1-6 is measured at 20±0.2°C and at 37°C±0.2°C as in Fig. 1 and Fig. 2 shown.

[0040] It is over Fig. 1 and Fig.2 that the viscosity of Working Examples 1-6 and Comparative Examples 4-6 is all below 100 mPa s at 20 ± 0.2°C and above 500 mPa s at 37 ± 0.2°C. Since the thickener is a non-temperature-sensitive material, the viscosity in Comparative Example 1 does not differ much between 20 ± 0.2°C and 37 ± 0.2°C, and the viscosity is all in the range of 500-600 mPa s. Comparative Example 2 has a viscosity of less than 300 mPa s at 37 ± 0.2°C due to a lower amount of added thickener. Comparative Example 3 has a viscosity of more than 130 mPa s at 20 ± 0.2°C due to a higher amount of added thickener.

[0041] The developing effect of the developing agents for gastrointestinal sonography prepared in Working Examples 1-6 and Comparative Examples 1-6 is tested as follows: For each group, four 500 mL bottles of samples were prepared and stored at 20 ± 0.2°C. The experimental animals were four Beagle dogs, male and female, 9–11 months old, weighing approximately 10 kg. The 500 mL samples were administered by swallowing at 20 ± 0.2°C for 15 minutes prior to imaging. Gastric and duodenal filling was monitored using ultrasound.

[0042] The evaluation is from 0 to 5 regarding the layer and structure of the gastric and duodenal wall, gastric and duodenal morphology, the display of peristalsis and emptying function, satisfaction with the window period and the elimination of the gas artifact effect, with the evaluation criteria shown in Table 2 below, and higher scores indicate better ability. Table 2 Evaluation criteria for the effect Item Score Evaluation criteria Layers and structures 0 point The layers and structures of the gastrointestinal wall are completely unrecognizable 1 point The layers and structures of the gastrointestinal wall are recognizable but difficult to distinguish 2 points To a certain extent, the layers and structures of the gastrointestinal wall are relatively difficult to distinguish. 3 points To a certain extent, the layers and structures of the gastrointestinal wall can be distinguished 4 points The layers and structures of the gastrointestinal wall can be distinguished relatively clearly 5 points The layers and structures of the gastrointestinal wall are clearly distinguishable morphology 0 point The morphology of the gastrointestinal tract is completely unrecognizable 1 point The morphology of all parts of the gastrointestinal tract is recognizable but difficult to distinguish 2 points To some extent, all parts of the gastrointestinal tract are relatively difficult to distinguish 3 points To a certain extent, all parts of the gastrointestinal tract can be distinguished 4 points All parts of the gastrointestinal tract can be distinguished relatively clearly 5 points All parts of the gastrointestinal tract can be clearly distinguished Display of peristalsis and emptying function 0 point Peristalsis and emptying of the gastrointestinal tract are completely unrecognizable 1 point Peristalsis and emptying function of the gastrointestinal tract are recognizable but difficult to assess 2 points To a certain extent, enteral peristalsis and emptying function of the gastrointestinal tract are relatively difficult to assess 3 points To a certain extent, enteral peristalsis and the emptying function of the gastrointestinal tract can be distinguished 4 points The peristalsis and the emptying function of the gastrointestinal tract can be distinguished relatively clearly 5 points The peristalsis and the emptying function of the gastrointestinal tract are clearly distinguishable Satisfaction with the effective examination window time 0 point The time of the gastric window is completely insufficient for observation 1 point The time of 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 3 points The time of the gastric window is just enough to meet the need for observation at normal speed 4 points The time of 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 removing gas artifacts 0 point The gas artifacts cannot be completely eliminated 1 point The gas artifacts can be easily removed, but the gas artifacts still affect the ultrasound observation of the gastrointestinal region. 2 points The gas artifacts can be removed moderately, but the effects of the gas artifacts on the Ultrasound observation of the gastrointestinal region is limited. 3 points The gas artifacts can be moderately eliminated, the gas artifacts no longer affect the ultrasound observation 4 points The gas artifacts must be significantly eliminated 5 points The gas artifacts must be completely eliminated Table 3 Development effect grouping Layers and structures Morphology Display of peristaltic and emptying function Satisfaction with the effective examination window time Effect of removing gas artifacts Average rating Execution example 1 5 5 5 5 5 5 Execution example 2 4.75 5 5 5 5 4.95 Execution example 3 5 5 5 4.75 5 4.95 Execution example 4 5 5 5 4.75 5 4.95 Execution example 5 4.75 5 5 5 5 4.95 Execution example 6 5 5 5 5 5 5 Comparison example 1 1 2.75 3 5 0 2.35 Comparison example 2 2 3 2.75 1.25 3 2.4 Comparison example 3 1 3 3 3 0 2 Comparison example 4 2.75 3 2.75 3 3.25 2.95 Comparison example 5 2.75 3.75 4 5 5 4.1 Comparison example 6 3 4 3.75 5 5 4.15

[0043] From Table 3, it can be seen that the average ratings of Working Examples 1-6 are all above 4.9, and from the various ratings, it can be seen that the development effects of the samples described in Working Examples 1-6 are as follows: the layers and structures of the gastrointestinal wall, the morphology of all parts of the gastrointestinal region, and the peristalsis and evacuation function of the gastrointestinal region can be almost completely and clearly distinguished; the gas artifacts can be completely eliminated; and there is sufficient gastric window time for observing the normal velocity. The average ratings of Comparative Example 1, Comparative Example 2, Comparative Example 3, and Comparative Example 4 are 2.35, 2.4, 2.95, and 2.95, respectively, which are much lower than the ratings of Working Examples 1-6.From the various evaluations, it can be seen that the viscosity of Comparative Example 1 is comparable to the final viscosity of the developing agent described in Working Examples 1-6 when it reaches the stomach due to the use of a conventional thickener to ensure the window period of the sample, but Comparative Example 1 has no viscosity change from 20±0.2°C to 37°C±0.2°C, therefore, it is difficult for the gas to leak out of the gastrointestinal tract at this viscosity, so that the ultrasound image shows a large number of gas artifacts that interfere with the ultrasound image, therefore Comparative Example 1 has a higher rating for the window period and all other ratings are lower.In Comparative Examples 2 and 3, although the viscosity increases from 20±0.2°C to 37±0.2°C, the viscosity at 20±0.2°C is also low or high due to the small or large amount of thickener added. Furthermore, the density of the solid particles differs from the liquid density of the sample. Even if shaken well, the product still has the problem of uneven ultrasound images after reaching the stomach, resulting in lower overall ratings. In Comparative Example 4, the solid contrast agent is not modified by biocompatible polymers, so it easily sinks in the stomach, resulting in highly echogenic interface inhomogeneity at the gastrointestinal ultrasound interface, and therefore, all its ratings are lower.The average evaluations of Comparative Example 5 and Comparative Example 6 are 4.1 and 4.15, respectively, which are relatively high, but observation of the evaluations shows that in the particle sizes of the solid contrast substance particles in Comparative Example 5 and Comparative Example 6, the silica particles of different particle sizes are not mixed in accordance with certain ratios, therefore, the scattering and reflection of particles are easy, and the evaluations of the layers and structures of the gastrointestinal wall, the morphology of all parts of the gastrointestinal region, and the peristalsis and emptying functions of the gastrointestinal region in the developing effect are lower than those of the working examples.

[0044] The embodiments described above do not represent all embodiments, but only a part of the embodiments. The detailed explanation of the embodiments of the present invention does not serve to limit the scope of the present invention, but only represents the selected embodiments of the present invention. All other embodiments obtained by the person skilled in the art based on the embodiments in the present invention without creative work should be considered to be covered by the scope of the present invention. QUOTES CONTAINED IN THE DESCRIPTION

[0000] This list of documents submitted by the applicant was generated automatically and is included solely for the convenience of the reader. This list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions. Cited patent literature

[0000] CN 102441180 B

[0005] CN 103611173 B

[0005] CN 1721000 A

[0005] CN 107115534 A

[0006] CN 109745570 A

[0006] CN 107055553 A

[0036] CN 108046276 A

[0036] Cited non-patent literature

[0000] Cheng Chunfeng, Jiacheng Li, Huiqiong Yan, Ruolin Liu, Chunxiu Wang, Qiang Lin, Activation of silica nanoparticles by alginate derivatives for the preparation of Pickering emulsions [J], Daily Chemical Industry, 2014, 44(05):241-246

[0036] Weikun Liu, Meng Zhang, Binglong Li, Xidong Guan, Mingshuang Sun, Yujing He, Chunxiao Wang, Baochang Zhao, Jimei Zhang, Preparation of functionalized mesoporous silica-loaded cisplatin nanomedicines and their killing effect on breast cancer cells [J], Academic Journal of Taishan Medical College, 2019, 40(11):801-805

[0036]

Claims

[1] Development agents for gastrointestinal sonography, characterized bythat it consists of the components in the following parts by weight: 2-4 parts of a thickener, 2-4 parts of an osmolality regulator, 1.5-2.5 parts of a solid contrasting substance, 0.02-0.04 parts of a defoamer, 0.03-0.05 parts of a taste corrector, 0.03-0.05 parts of a preservative, 89.36-94.42 parts of purified water; wherein the solid contrasting substance has the same density as the liquid density of the developing agent; and wherein the thickener is one or more of Poroxam 407, Poroxam 338, Poroxam 237 and Poroxam 188; and wherein the solid contrasting substance is biocompatible polymer-modified silica particles; and wherein the biocompatible polymer is one or more of polyethylene glycol, branched polyethylene glycol, chitosan, alginate, hyaluronic acid, and polysiloxane;and wherein the silica particles are a mixture of silica particles of different particle sizes in a specific ratio; and wherein the specific formula is: silica particles of particle sizes 75-85 mesh, 85-95 mesh, 95-105 mesh, and 105-120 mesh are mixed in the mass ratio of (60-65):(15-20):(5-10):(5-20) to be homogeneously mixed; and wherein the preservative is sodium deoxyacetate. [2] Developing agent for gastrointestinal sonography according to claim 1, characterized by that the osmolality regulator is at least one of xylitol, mannitol. [3] Developing agent for gastrointestinal sonography according to claim 1, characterized by that the biocompatible polymer modifies the silica particles by one or more of sol-gel process, one-step post-grafting process, two-step post-grafting process and selective post-grafting process. [4] Developing agent for gastrointestinal sonography according to claim 1, characterized by that the defoamer is at least one of an organosilicon defoamer and a polyether defoamer; wherein the flavor corrector is one or more of strawberry flavor, lemon flavor, and apple flavor. [5] Developing agent for gastrointestinal sonography according to claim 4, characterized by that the organosilicon defoamer is dimethylsiloxane and the polyether defoamer is polyoxypropylene ethylene oxide glycerol ether. [6] Developing agent for gastrointestinal sonography according to any one of claims 1-5, characterized bythat the gelling temperature of the developing agent is 20-30°C, wherein the viscosity of the developing agent is lower at temperatures below the gelling temperature, and wherein the viscosity of the developing agent increases at temperatures above the gelling temperature; and wherein the viscosity of the developing agent is less than or equal to 100 mPa s at 20±0.2°C and greater than or equal to 500 mPa s at 37°C±0.2°C. [7] A process for preparing a developing agent for gastrointestinal sonography according to any one of claims 1 to 6, characterized bythat it comprises the following steps: taking purified water, controlling its temperature at 2-4°C, slowly adding a thickener, a defoamer, a flavor corrector and a preservative in sequence at 800-1200 rpm, and then adjusting the speed to 50-100 rpm, slowly adding a solid contrast substance, and then adjusting the speed to 800-1200 rpm, adding an osmolality regulator, stirring for 20-40 min, finally filling into a 500 mL brown polyester bottle to obtain a developing agent for gastrointestinal sonography.

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