Preparation and formulation method for a ready-to-use liquid oral gastric ultrasound contrast agent based on magnesium aluminum silicate and microcrystalline cellulose.

Abstract

This invention discloses a method for formulating and preparing a ready-to-use liquid oral gastric ultrasound contrast agent based on magnesium aluminum silicate and microcrystalline cellulose, belonging to the technical field of medical ultrasound diagnostic reagents. Through extensive in vitro and intracellular screening experiments, complex formulations of materials such as magnesium aluminum silicate, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal microcrystalline cellulose, polyethylene glycol, and xylitol were screened, and in vitro and intracellular ultrasound contrast imaging was subsequently performed. Ultimately, it was confirmed that selecting a complex formulation of magnesium aluminum silicate, colloidal microcrystalline cellulose, and pectin not only provides excellent suspension properties but also eliminates the occurrence of bright spot clusters in intracellular contrast imaging, while polyethylene glycol improves real-time image quality as an antifoaming agent. The ultrasound contrast agent formulation disclosed in this invention maintains extremely high thixotropy and stability, as well as very good ultrasound contrast quality, while also retaining the product characteristic of being ready for immediate use, making it extremely convenient for clinical use.

Description

[Technical Field]

[0001] This invention belongs to the field of medical ultrasound diagnostic reagents, and more specifically, to a method for compounding and preparing a ready-to-use liquid oral gastric ultrasound contrast agent based on magnesium aluminum silicate and microcrystalline cellulose. [Background technology]

[0002] The technical problem that this invention aims to solve is the shortcomings of Patent Document 1. Using Patent Document 1 as a comparative patent, this invention relates to the formulation and preparation method of a ready-to-use oral gastric ultrasound contrast agent, invented to achieve the best possible contrast quality of ultrasound contrast agents within the human body. In Patent Document 1, when contrast is performed in the body, as the examination time progresses, a "bright spot cluster" phenomenon (echoes appearing as high-echo clusters under ultrasound) may gradually appear in the contrast agent within the subject's stomach. This "bright spot cluster" phenomenon affects gastric ultrasound observation, causing uneven echo distribution within the contrast agent and posterior echo attenuation, affecting the observation of the stomach wall and ultimately impacting the effectiveness of the gastric ultrasound examination. In in-vivo contrast, the amount of this type of "bright spot cluster" varies from case to case, and the degree of impact on ultrasound contrast varies from minor to significant, sometimes even making it difficult to continue the gastric ultrasound examination. To improve the stability of gastric ultrasound contrast and reduce the effects of individual differences, resolving the "bright spot cluster" phenomenon is necessary and important. The analysis of the bright spot phenomenon may be related to factors such as gastric juice in the stomach, mucus and small air bubbles in the gastric juice, air bubbles that enter during oral ingestion, aggregation of the contrast agent, and expulsion of the contrast agent by gastric peristalsis. [Prior art documents] [Patent Documents]

[0003] [Patent Document 1] Chinese patent CN108939097B specification [Overview of the project]

[0004] In view of the shortcomings of the prior art, the present invention provides a method for compounding and preparing a ready-to-use liquid oral gastric ultrasound contrast agent, mainly based on magnesium aluminum silicate and microcrystalline cellulose.

[0005] To achieve the objectives of the above invention, the present invention employs the following technical methods.

[0006] The present invention provides a ready-to-use liquid oral gastric ultrasound contrast agent, characterized in that magnesium aluminum silicate is added as a compound formulation thickening and suspension aid to the contrast agent formulation.

[0007] Furthermore, the above-mentioned compound thickening and suspension aid also contains colloidal cellulose and pectin.

[0008] Furthermore, the above-mentioned contrast agent is also used in the preparation of gastric ultrasound contrast agents.

[0009] The present invention also provides a ready-to-use liquid oral gastric ultrasound contrast agent, characterized by comprising a compound thickening suspension aid, ultrasound contrast-enhancing particulate matter, an antifoaming agent, a flavoring agent, a preservative, and water.

[0010] Furthermore, the above-mentioned compound thickening and suspension aid consists of magnesium aluminum silicate, colloidal cellulose, and pectin.

[0011] Furthermore, the dosage (w / w) range of the above magnesium aluminum silicate is 0.01% to 3.0%, with a preferred range of 0.05% to 1.0%, which provides optimal gastric ultrasound contrast. The magnesium aluminum silicate used in the formulation is of type IA, IB, IC, IIA (classification types in the 2020 edition of the Chinese Pharmacopoeia), and any mixture of two or more of these, of which the preferred magnesium aluminum silicate types are type IA and IC.

[0012] The dose (w / w) range of the above-mentioned colloidal cellulose is 0.01% to 3.0%, with a preferred range of 0.05% to 1.0%, which provides optimal gastric ultrasound contrast. The types of colloidal cellulose used are Avicel RC-501, Avicel RC-581, Avicel RC-591, Avicel CL-611, and any mixture of two or more of these, of which Avicel RC-591 and Avicel CL-611 are preferred.

[0013] The recommended dose (w / w) range for pectin is 0.01% to 1.0%, with a preferred range of 0.05% to 0.5%, which provides optimal ultrasound contrast enhancement of the stomach.

[0014] Furthermore, the above-mentioned defoaming agent is one or more of polyethylene glycol, simethicone, and simethicone emulsion.

[0015] Furthermore, the ultrasonic contrast-enhanced particulate matter is microcrystalline cellulose or silicified microcrystalline cellulose. Microcrystalline cellulose is a highly echogenic particulate matter with a particle size (D50) of 20 to 150 μm, preferably microcrystalline cellulose with a particle size (D50) of 50 to 110 μm. The dosage range (w / w) of the microcrystalline cellulose used is 1 to 20%, and the preferred usage range (w / w) is 2 to 10%.

[0016] Furthermore, the above-mentioned contrast agent can be used in the preparation of gastric ultrasound contrast agents.

[0017] The present invention further provides a method for preparing a ready-to-use liquid oral gastric ultrasound contrast agent as described above, and is characterized by comprising the following steps: (1) Weigh out the required amount of magnesium aluminum silicate, add an appropriate amount of water, stir at 80°C to hydrate, then homogenize, and let it cool to room temperature before setting it aside. (2) Weigh microcrystalline cellulose in the compounding amount, add an appropriate amount of water, stir to mix uniformly, and degas. (3) Weigh polyethylene glycol in the prescribed amount, add an appropriate amount of water, and allow it to dissolve completely. (4) Weigh colloidal microcrystalline cellulose and pectin in the prescribed amount, add an appropriate amount of water, stir to disperse uniformly, then stand for homogenization. (5) Weigh additives including flavoring agents, preservatives and the like in the compounding amount, add an appropriate amount of water to disperse and dissolve the additives, then degas. (6) Add the materials obtained in steps (2), (3) and (4) all at once to the magnesium aluminum silicate suspension obtained in (1), after homogenization, add the material obtained in (5) and stir uniformly. Then add the essence in the compounding amount, the remaining water and other components respectively, and stir uniformly. (7) Degas the mixture and fill it into containers.

[0018] Furthermore, the contrast agent obtained by the above preparation method is applied to the preparation of gastric ultrasound contrast agents.

[0019] The composite compounded thickening suspension aid of the present invention can maintain the suspension uniformity during storage of ready-to-use oral gastric ultrasound contrast agents and the ease of dilution after adding water. More importantly, it can eliminate the "bright spot cluster" phenomenon in images during in vivo contrast enhancement, greatly improve image definition, and improve diagnostic accuracy.

[0020] Compared with the prior art, the present invention has the following advantages and beneficial effects.

[0021] (1) The applicant uses magnesium aluminum silicate and colloidal microcrystalline cellulose in composite blending for the first time, which eliminates the bright spot cluster phenomenon that easily occurs during in vivo contrast enhancement of the product of the prior art (CN108939097B), and significantly prolongs the observable contrast enhancement time.

[0022] (2) The formulation of the ultrasound contrast agent disclosed in this invention can reduce the time it takes for the ultrasound image to recover to an ideal state after intense vibration to less than one minute, thereby better eliminating the effect of air bubbles on the ultrasound image and further meeting the requirements for ultrasound contrast during clinical examinations.

[0023] (3) The ultrasound contrast agent disclosed in the present invention maintains excellent thixotropy and excellent stability, while also retaining the characteristics of being ready for immediate use, making it very convenient for clinical use.

[0024] (4) The ready-to-use oral gastric ultrasound contrast agent disclosed in the present invention not only possesses the above-mentioned clear advantages, but also completely retains the advantages of the prior art (CN108939097B). For example, it is highly safe, has no toxic side effects, has a uniform particle distribution, a long shelf life, a pleasant taste, is easy to swallow, is easy to prepare and drink, can quickly remove small air bubbles and mucus interference adhering to the stomach wall, and is cost-controllable. [Brief explanation of the drawing]

[0025] [Figure 1] Figure 1 shows the ultrasound findings from an in vitro contrast-enhanced screening experiment. In A, after a violent vibration, interference from a large number of bubbles is observed within the contrast agent, and the internal echo is non-uniform. In B and C, the bubbles disperse over time, and the interference from bubbles within the contrast agent gradually decreases. In D, the bubbles completely disappear, and the echo within the contrast agent returns to a uniform state. The time from the violent vibration to the ultrasound findings in Figure D is recorded as the time it takes for the image to recover to an ideal state after the violent vibration.

[0026] [Figure 2]Figure 2 shows the effect of bright spot clusters on ultrasound images. In real-time ultrasound image A, where contrast agent was administered orally, there are 10 points, and the internal echo is uniform. However, in image a, taken 20 minutes later, a small amount of bright spot clusters are visible inside, mildly affecting contrast enhancement. In real-time image B, there are 10 points, and the internal echo is uniform. However, in image b, taken 20 minutes later, a moderate amount of bright spot clusters are visible inside, moderately affecting contrast enhancement. In real-time image C, there are 10 points, and the internal echo is uniform. However, in image a, taken 30 minutes later, a large amount of bright spot clusters are visible inside, severely affecting contrast enhancement.

[0027] [Figure 3] Figure 3 shows the effect of the cluster of bright spots in the first round of samples on ultrasound images. The real-time ultrasound image of sample A, administered orally with contrast agent, shows 10 points, and the internal echo is uniform. However, at 20 minutes later, sample a shows a small cluster of bright spots internally, slightly affecting contrast enhancement. The real-time image of sample B also shows 10 points, and the internal echo is uniform. However, at 20 minutes later, sample b shows a small cluster of bright spots internally, slightly affecting contrast enhancement. The real-time image of sample C shows 10 points, and the internal echo is uniform. At 20 minutes later, the internal area of ​​sample c showed almost no cluster of bright spots, indicating little to no effect on contrast enhancement.

[0028] [Figure 4] Figure 4 shows the effect of the clusters of bright spots in the first round of samples on ultrasound images. The real-time ultrasound image of sample A, administered orally with contrast agent, shows 10 points, and the internal echo is uniform. However, at 20 minutes later (a), a small cluster of bright spots is visible inside, slightly affecting the contrast enhancement. The real-time image of sample B shows 10 points, and the internal echo is uniform. However, at 20 minutes later (b), a small cluster of bright spots is visible inside, slightly affecting the contrast enhancement. The real-time image of sample C shows 10 points, and the internal echo is uniform. However, at 20 minutes later (c), an examination of the interior reveals a small cluster of bright spots, slightly affecting the contrast enhancement.

[0029] [Figure 5]Figure 5 shows the findings of ultrasound images of samples from the second round that were compounded with polyethylene glycol. The real-time ultrasound images of the left image (ABCDEF) after oral administration of contrast agent show 10 points and the internal echo is uniform, but the right image (abcdef) taken 20 minutes later still shows a small number of bright spots within, slightly affecting the contrast enhancement.

[0030] [Figure 6] Figure 6 shows the ultrasound findings of the third round sample. The real-time ultrasound images of the left image (ABCDEF) after oral administration of contrast agent show 10 points, and the internal echo is uniform. However, the right image (abcdef) taken 20 minutes later still shows a small number of bright spots within the sample, slightly affecting the contrast enhancement.

[0031] [Figure 7] Figure 7 shows the ultrasound findings of the third round sample. The real-time ultrasound images of the left image (ABCDEF) after oral administration of contrast agent show 10 points, and the internal echo is uniform. However, the right image (abcdef) taken 20 minutes later shows a small number of bright spots within the sample, which slightly affected the contrast enhancement.

[0032] [Figure 8] Figure 8 shows the ultrasound findings of the third round sample. The real-time ultrasound images of the left image (ABCDEF) after oral administration of contrast agent show 10 points, and the internal echo is uniform. However, the right image (abcdef) taken 20 minutes later shows a small number of bright spots within the sample, which slightly affected the contrast enhancement.

[0033] [Figure 9] Figure 9 shows the ultrasound findings of the fourth round sample. The real-time ultrasound images on the left (ABCD), taken after oral administration of contrast agent, show 10 points, with a more uniform and detailed internal echo, and a clearer image of the stomach wall. In the right (abcd) images, after half of the contrast agent had been emptied from the stomach, no clusters of bright spots were observed internally, indicating no impact on contrast enhancement.

[0034] [Figure 10]Figure 10 shows the ultrasound findings of the fifth round sample. The real-time ultrasound image on the left, ABCDE, after oral administration of contrast agent, shows 10 points, with a uniform and finer internal echo, and a clearer image of the stomach wall. In the right image abcde, after half of the contrast agent had been emptied from the stomach, no bright spots were observed internally, indicating no impact on contrast enhancement.

[0035] [Figure 11] Figure 11 shows the ultrasound findings of the fifth round sample. The real-time ultrasound image on the left (ABCDE), after oral administration of contrast agent, shows 10 points, with a uniform and finer internal echo, and a clearer image of the stomach wall. In the right (abcde) image, after half of the contrast agent had been emptied from the stomach, no clusters of bright spots were observed internally, indicating no impact on contrast enhancement.

[0036] [Figure 12] Figure 12 shows the ultrasound findings of the fifth round sample. The real-time ultrasound image on the left (ABCDE), after oral administration of contrast agent, shows 10 points, with a uniform and finer internal echo, and a clearer image of the stomach wall. In the right (abcde) image, after half of the contrast agent had been emptied from the stomach, no clusters of bright spots were observed internally, indicating no impact on contrast enhancement.

[0037] [Figure 13]Figure 13 compares the intracellular and extracellular contrast enhancement effects of ultrasound in Example 3 and Example 1 of the prior art (CN108939097B). A is a comparison of extracellular contrast enhancement, with Example 3 on the left and Example 1 of the prior art (CN108939097B) on the right. The ultrasound 5 minutes after vigorous vibration shows that the internal echoes are uniform in both extracellular contrast enhancements. B (Example 3) shows that the ultrasound image is superior to b (Example 1 of the prior art CN108939097B), with more uniform internal echoes, fewer bubbles adhering to the stomach wall, and a clearer image of the stomach wall. As the observation time progresses, C (Example 3) shows that the ultrasound image remains uniform up to the halfway point of gastric emptying, and no bright spots appear. However, c (Example 1 of the prior art CN108939097B) shows that the ultrasound image deteriorates progressively, with interference from many bright spots even appearing, significantly affecting the representation of the stomach wall.

[0038] [Figure 14] Figure 14 compares the intracellular and extracellular contrast enhancement effects of the ultrasound in Example 3 (left image) and the commercially available product (right image). A is a comparison of extracellular contrast enhancement, with Example 3 on the left and the commercially available product on the right. The internal echoes are uniform in both cases. B (Example 3) and b (commercial product) are comparison images of short-axis ultrasound images of the gastric body. C (Example 3) and c (commercial product) are comparison images of oblique cross-sections of the gastric fundus. D (Example 3) and d (commercial product) are comparison images of annular ultrasound images of the gastric angle. E (Example 3) and e (commercial product) are examination findings after 20 minutes. Both real-time ultrasound images show 10 points, and the internal echoes are uniform in both cases. However, the left image (Example 3) shows slightly less posterior echo attenuation than the right image (commercial product), and the gastric wall is more clearly visible. Throughout the entire examination process, neither image showed any influence from bright spot clusters.

[0039] [Figure 15] Figure 15 shows the results of a comprehensive scan of the gastric fundus, gastric body, gastric angle, gastric sinus (long axis, short axis, and annular plane) using a five-stage, nine-plane gastric ultrasound technique after oral administration to volunteers.

[0040] [Figure 16] Figure 16 shows the intracellular gastric ultrasound contrast enhancement effect in Examples 4-7. Left-hand images A (Example 4), B (Example 5), C (Example 6), and D (Example 7) show 10 real-time gastric ultrasound images after oral administration. The internal echoes are uniform and detailed in all images, and the gastric wall is clearly visible. Right-hand images a (Example 4), b (Example 5), c (Example 6), and d (Example 7) show that up to the halfway point of gastric emptying, there are no bright spots within the contrast agent due to gastric ultrasound, the contrast enhancement is unaffected, and the gastric wall is clearly visible.

[0041] [Figure 17] Figure 17 shows the intracellular gastric ultrasound contrast enhancement effect in Examples 8-11. Left-hand images A (Example 8), B (Example 9), C (Example 10), and D (Example 11) show 10 real-time gastric ultrasound images after oral administration. The internal echoes are uniform and detailed in all images, and the gastric wall is clearly visible. Right-hand images a (Example 8), b (Example 9), c (Example 10), and d (Example 11) show that up to the halfway point of gastric emptying, gastric ultrasound does not reveal any clusters of bright spots within the contrast agent, does not affect the contrast enhancement, and the gastric wall is clearly visible.

[0042] [Figure 18] Figure 18 shows the intracellular gastric ultrasound contrast enhancement effect in Examples 12-15. Left-hand images A (Example 12), B (Example 13), C (Example 14), and D (Example 15) show 10 real-time gastric ultrasound images after oral administration. The internal echoes are uniform and detailed in all images, and the gastric wall is clearly visible. Right-hand images a (Example 12), b (Example 13), c (Example 14), and d (Example 15) show that up to the halfway point of gastric emptying, gastric ultrasound does not reveal any bright spots within the contrast agent, does not affect the contrast enhancement, and the gastric wall is clearly visible.

[0043] [Figure 19]Figure 19 shows the intracellular gastric ultrasound contrast enhancement effect in Examples 16-20. Left-hand images A (Example 16), B (Example 17), C (Example 18), and D (Example 19) show 10 real-time gastric ultrasound images after oral administration. The internal echoes are uniform and detailed in all images, and the gastric wall is clearly visible. Right-hand images a (Example 16), b (Example 17), c (Example 18), and d (Example 19) show that up to the halfway point of gastric emptying, gastric ultrasound does not reveal any bright spots within the contrast agent, does not affect the contrast enhancement, and the gastric wall is clearly visible. [Modes for carrying out the invention]

[0044] The present invention will be described in more detail below through specific examples and drawings. The following examples are merely for the purpose of further illustrating the present invention and should not be understood as limiting the present invention. [Examples]

[0045] Example 1

[0046] Referring to comparative studies using CN108939097B as a comparative patent, the applicant first conducted an in vitro ultrasound contrast screening experiment. The evaluation indicators mainly included 1) the score of real-time in vitro ultrasound contrast after preparation in the usual manner, and 2) the time it took for the ultrasound image to return to a uniform echo and no longer be affected by bubbles after the bottle was vigorously shaken and a large number of bubbles were generated. In this experiment, the applicant simulated and considered how the swallowing motion of a person can cause bubbles to form in the contrast agent, adversely affecting contrast imaging.

[0047] While the real-time in vitro ultrasound contrast imaging scores in the comparative patent CN108939097B are nearly perfect (10 out of 10), the time it takes for the ultrasound image to recover to an ideal state after vigorous shaking exceeds 10 minutes in all cases. Therefore, by optimizing the concentration of colloidal microcrystalline cellulose in the CN108939097B patent document and using a new composite formulation material, a suspension aid, we were able to reduce the interference of bubbles generated after five vigorous shakes to less than one minute, allowing the image to recover to an ideal state. This more effectively eliminates the effect of bubbles on the ultrasound image and further meets the requirements of ultrasound contrast imaging in clinical examinations. To this end, the applicant conducted in vitro contrast screening experiments, including the use of composite formulations of colloidal microcrystalline cellulose and materials such as polyethylene glycol (different molecular weight types), polypropylene glycol, xylitol, fructose, magnesium aluminum silicate, and pectin. The process of the in vitro ultrasound contrast screening experiment is shown in Figure 1. Results from in vitro ultrasound contrast-enhanced screening experiments showed that composite formulations of colloidal microcrystalline cellulose (0.05-1.0%), polyethylene glycol (1%-7%), xylitol (1%-7%), fructose (1%-7%), magnesium aluminum silicate (0.05-1.0%), and pectin (0.05-0.5%) (and other materials) could almost completely overcome the adverse effects of air bubbles generated by swallowing simulations. Table 1 lists only the experimental data for eight representative viable samples.

[0048] Table 1. Data from in vitro ultrasound contrast-enhanced experiments on some samples [Table 1]

[0049] The contrast-enhancing particulate matter in the eight representative samples listed in Table 1 consists of 8% (w / w) microcrystalline cellulose PH102, 0.1% potassium sorbate by mass fraction, 0.05% citric acid by mass fraction, 0.03% sucralose by mass fraction, and 0.5% cocoa powder by mass fraction, and the composition of the suspension aids is as follows. Sample 1 (in vitro): Colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IC 0.2% + pectin 0.1%; Sample 2 (in vitro): Colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 1500 5.0% + pectin 0.1%; Sample 3 (in vitro): Colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 4000 5.0% + pectin 0.1%; Sample 4 (extracorporeal): Colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 5.0% + pectin 0.1%; Sample 5 (extracorporeal): Colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 8000 5.0% + pectin 0.1%; Sample 6 (extracorporeal): Colloidal microcrystalline cellulose RC591 0.5% + Polypropylene glycol 4000 5.0% + Pectin 0.1%; Sample 7 (in vitro): Colloidal microcrystalline cellulose RC591 0.5% + xylitol 4.0% + pectin 0.1%; Sample 8 (in vitro): Colloidal microcrystalline cellulose RC591 0.5% + fructose 4.0% + pectin 0.1%.

[0050] Example 2

[0051] Based on the above in vitro screening experiments, the applicant conducted screening experiments on large quantities of contrast agents for intracellular gastric ultrasound imaging, including composite formulations of materials such as microcrystalline cellulose, silicified microcrystalline cellulose, colloidal microcrystalline cellulose, magnesium aluminum silicate, polyethylene glycol, xylitol, fructose, and pectin. The focus of the study was on intracellular gastric ultrasound imaging effects and the phenomenon of bright spots. The evaluation indicators for the intracellular contrast screening experiments mainly included: 1) real-time image quality score (including the deduction for internal echo coarseness and air bubbles adhering to the gastric wall), 2) presence or absence of bright spots, the duration of their appearance, and the degree to which they affect the image (minor, moderate, or significant), and 3) gastric emptying time of the contrast agent.

[0052] In the first round of in-vivo contrast screening experiments, the type of auxiliary material to be added was screened in order to solve the bright spot cluster problem. The results for some samples in which the effect of the bright spot cluster was minor are shown in Table 2. Other non-ideal samples in which the effect of the generated bright spot cluster reached moderate to severe are not listed in this patent specification due to space limitations. Figure 2 shows in-vivo ultrasound findings in which the bright spot cluster had a minor, moderate, or severe effect on the ultrasound image.

[0053] Table 2. Intracellular ultrasound contrast-enhanced experimental data for some samples [Table 2]

[0054] Table 2 lists six representative samples (composition ratios are by mass fraction): The contrast-enhancing particulate matter consists of 8% microcrystalline cellulose PH102, 0.1% potassium sorbate, 0.05% citric acid, 0.03% sucralose, 0.5% cocoa powder, and 0.2% simethicone emulsion (30%). The component composition of the suspending aids used in the compound formulation is as follows.

[0055] First round intracellular sample 1: Colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 1500 5.0% + pectin 0.1%. The findings from the intracellular ultrasound images are shown in Figure 3A (real-time findings) and Figure 3a (findings after 20 minutes).

[0056] First round intracellular sample 2: Colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 4000 5.0% + pectin 0.1%. The findings from the intracellular ultrasound images are shown in Figure 3B (real-time findings) and Figure 3b (findings after 20 minutes).

[0057] First round intracellular sample 3: Colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 5.0% + pectin 0.1%. Findings from intracellular ultrasound images are shown in Figure 3C (real-time findings) and Figure 3C (findings after 20 minutes).

[0058] First round intracellular sample 4: Colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 8000 5.0% + pectin 0.1%. The findings from the intracellular ultrasound images are shown in Figure 4A (real-time findings) and Figure 4a (findings after 20 minutes).

[0059] First round intracellular sample 5: Colloidal microcrystalline cellulose RC591 0.5% + xylitol 4.0% + pectin 0.1%. Findings from intracellular ultrasound images are shown in Figure 4B (real-time findings) and Figure 4b (findings after 20 minutes).

[0060] First round intracellular sample 6: Colloidal microcrystalline cellulose RC591 0.5% + fructose 4.0% + pectin 0.1%. Findings from intracellular ultrasound images are shown in Figure 4C (real-time findings) and Figure 4C (findings after 20 minutes).

[0061] The first round of in-vivo contrast-enhanced screening experiments revealed that the bright spot phenomenon could be mitigated by further reducing the concentration of colloidal microcrystalline cellulose and by compounding it with substances such as polyethylene glycols, fructose, and pectin. In particular, the effect of PEG6000 was most pronounced, so the second round of in-vivo contrast-enhanced screening experiments was conducted to screen for optimal PEG6000 concentrations.

[0062] The second round of PEG6000 concentration screening samples (composition ratios are by mass fraction) consisted of 8% microcrystalline cellulose PH102, 0.1% potassium sorbate, 0.05% citric acid, 0.03% sucralose, 0.5% cocoa powder, and 0.2% simethicone emulsion (30%). The component composition of the combined suspension aids and the resulting images are as follows.

[0063] Second round intracellular sample 1: Colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 1.0% + pectin 0.1%. Findings from intracellular ultrasound images are shown in Figure 5A (real-time findings) and Figure 5a (findings after 20 minutes).

[0064] Second round intracellular sample 2: Colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 2.0% + pectin 0.1%. Findings from intracellular ultrasound images are shown in Figure 5B (real-time findings) and Figure 5b (findings after 20 minutes).

[0065] Second round intracellular sample 3: Colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 3.0% + pectin 0.1%. Findings from intracellular ultrasound images are shown in Figure 5C (real-time findings) and Figure 5C (findings after 20 minutes).

[0066] Second round intracellular sample 4: Colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 4.0% + pectin 0.1%. Findings from intracellular ultrasound images are shown in Figure 5D (real-time findings) and Figure 5d (findings after 20 minutes).

[0067] Second round intracellular sample 5: Colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 5.0% + pectin 0.1%. Findings from intracellular ultrasound images are shown in Figure 5E (real-time findings) and Figure 5f (findings after 20 minutes).

[0068] Second round intracellular sample 6: Colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 6.0% + pectin 0.1%. Findings from intracellular ultrasound images are shown in Figure 5F (real-time findings) and Figure 5f (findings after 20 minutes).

[0069] In the second round of in-vivo screening experiments described above, the real-time image quality score for all samples was 10 points, but the effect of bright spots was still occasionally observed (albeit to a minor degree), and the gastric emptying time of the contrast agent was around 20 minutes, similar to the results of the first round. From the experimental results, it was found that the concentration of PEG6000 was not the main influencing factor of bright spots, so a third round of in-vivo contrast screening experiments was conducted to screen composite formulations of PEG6000 and other auxiliary materials.

[0070] Round 3: Screening of composite formulations of in vivo PEG6000 samples with other auxiliary materials (composition ratios are by mass fraction): The contrast-enhancing particulate matter consisted of 8% microcrystalline cellulose PH102, 0.1% potassium sorbate, 0.05% citric acid, 0.03% sucralose, 0.5% cocoa powder, and 0.2% simethicone emulsion (30%). The component composition of the suspension aids used in the composite formulation and the resulting images are as follows.

[0071] Third round intracellular sample 1: Colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 1.0% + xylitol 2.0% + pectin 0.1%. The findings from the intracellular ultrasound images are shown in Figure 6A (real-time findings) and Figure 6a (findings after 20 minutes).

[0072] Third round intracellular sample 2: Colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 1.0% + xylitol 3.0% + pectin 0.1%. The findings from the intracellular ultrasound images are shown in Figure 6B (real-time findings) and Figure 6b (findings after 20 minutes).

[0073] Third round intracellular sample 3: Colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 1.0% + xylitol 4.0% + pectin 0.1%. Findings from intracellular ultrasound images are shown in Figure 6C (real-time findings) and Figure 6C (findings after 20 minutes).

[0074] Third round intracellular sample 4: Colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 1.0% + xylitol 5.0% + pectin 0.1%. The findings from the intracellular ultrasound images are shown in Figure 6D (real-time findings) and Figure 6d (findings after 20 minutes).

[0075] Third round intracellular sample 5: Colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 5.0% + xylitol 2.0% + pectin 0.1%. Findings from intracellular ultrasound images are shown in Figure 6E (real-time findings) and Figure 6e (findings after 20 minutes).

[0076] Third round intracellular sample 6: Colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 5.0% + xylitol 3.0% + pectin 0.1%. The findings from the intracellular ultrasound images are shown in Figure 7A (real-time findings) and Figure 7a (findings after 20 minutes).

[0077] Third round intracellular sample 7: Colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 5.0% + xylitol 4.0% + pectin 0.1%. The findings from the intracellular ultrasound images are shown in Figure 7B (real-time findings) and Figure 7b (findings after 20 minutes).

[0078] Third round intracellular sample 8: Colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 5.0% + xylitol 5.0% + pectin 0.1%. The findings from the intracellular ultrasound images are shown in Figure 7C (real-time findings) and Figure 7C (findings after 20 minutes).

[0079] Third round intracellular sample 9: Colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 1.0% + fructose 2.0% + pectin 0.1%. Findings from intracellular ultrasound images are shown in Figure 7D (real-time findings) and Figure 7d (findings after 20 minutes).

[0080] Third round intracellular sample 10: Colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 1.0% + fructose 3.0% + pectin 0.1%. The findings from intracellular ultrasound imaging are shown in Figure 7E (real-time findings) and Figure 7e (findings during partial gastric emptying of contrast agent).

[0081] Third round intracellular sample 11: Colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 1.0% + fructose 4.0% + pectin 0.1%. The findings from the intracellular ultrasound images are shown in Figure 8A (real-time findings) and Figure 8a (findings after 20 minutes).

[0082] Third round intracellular sample 12: Colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 1.0% + fructose 5.0% + pectin 0.1%. The findings from the intracellular ultrasound images are shown in Figure 8B (real-time findings) and Figure 8b (findings after 20 minutes).

[0083] Third round intracellular sample 13: Colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 5.0% + fructose 2.0% + pectin 0.1%. Findings from intracellular ultrasound images are shown in Figure 8C (real-time findings) and Figure 8C (findings after 20 minutes).

[0084] Third round intracellular sample 14: Colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 5.0% + fructose 3.0% + pectin 0.1%. The findings from the intracellular ultrasound images are shown in Figure 8D (real-time findings) and Figure 8d (findings after 20 minutes).

[0085] Third round intracellular sample 15: Colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 5.0% + fructose 4.0% + pectin 0.1%. The findings from the intracellular ultrasound images are shown in Figure 8E (real-time findings) and Figure 8e (findings after 20 minutes).

[0086] In the third round of in-vivo screening experiments, all samples had a real-time image quality score of 10, but there were still small clusters of bright spots, which had a mild effect on ultrasound contrast, and the gastric emptying time of the contrast agent was around 20 minutes. From the results of the third round of in-vivo screening experiments, it was found that the composite formulation of polyethylene glycol, xylitol, and fructose still had small clusters of bright spots, which had a mild effect on ultrasound contrast, and that the bright spot phenomenon could not be completely eliminated. Therefore, a fourth round of in-vivo contrast screening experiments was conducted (adding a different type of aluminum magnesium silicate).

[0087] In the fourth round of in vivo contrast screening of different types of magnesium aluminum silicate samples (composition ratios are by mass fraction): The contrast-enhancing particulate matter consisted of 8% microcrystalline cellulose PH102, 0.1% potassium sorbate, 0.05% citric acid, 0.03% sucralose, 0.5% cocoa powder, and 0.2% simethicone emulsion (30%). The component composition of the suspension aids used in the compound formulation and the resulting images are as follows.

[0088] Fourth round intracellular sample 1: Colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IC 0.4% + pectin 0.1%. The findings from the intracellular ultrasound images are shown in Figure 9A (real-time findings) and Figure 9a (findings after 20 minutes).

[0089] Fourth round intracellular sample 2: Colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IB 0.4% + pectin 0.1%. Findings from intracellular ultrasound images are shown in Figure 9B (real-time findings) and Figure 9b (findings after 20 minutes).

[0090] Fourth round intracellular sample 3: Colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IC 0.4% + pectin 0.1%. Findings from intracellular ultrasound images are shown in Figure 9C (real-time findings) and Figure 9C (findings after 20 minutes).

[0091] Fourth round intracellular sample, extracellular 4: Colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IA 1.0% + pectin 0.1%. The findings from the intracellular ultrasound images are shown in Figure 9D (real-time findings) and Figure 9d (findings after 20 minutes).

[0092] In the fourth round of in-vivo screening experiments, the real-time image quality score for all samples was 10 points (and the reduction in roughness / effect of air bubbles was even better), the gastric emptying time of the contrast agent was around 20 minutes, and in all samples, the bright spot phenomenon did not appear until the gastric ultrasound contrast agent was completely emptied from the stomach. From the results of the fourth round of in-vivo screening experiments described above, it was found that aluminum magnesium silicate can effectively resolve the bright spot phenomenon, and in all samples, the bright spot phenomenon did not appear until the gastric ultrasound contrast agent was completely emptied from the stomach, and the real-time images were finer, with the stomach wall appearing more clearly. In order to obtain a higher ultrasound contrast effect, the effect of various types of aluminum magnesium silicate, colloidal microcrystalline cellulose RC591, and polyethylene glycol on removing bright spots was investigated, and the fifth round of in-vivo screening experiments was conducted.

[0093] In the fifth round of in vivo samples, we investigated the effect of compound formulations of different types of aluminum magnesium silicate, colloidal microcrystalline cellulose RC591, and polyethylene glycol on removing bright spots (compound ratios are by mass fraction): the contrast-enhancing particulate matter consisted of 8% microcrystalline cellulose PH102, 0.1% potassium sorbate, 0.05% citric acid, 0.03% sucralose, 0.5% cocoa powder, and 0.2% simethicone emulsion (30%). The component composition of the suspension aids used in the compound formulation and the resulting images are as follows.

[0094] Round 5 Intracellular Sample 1: Colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IA 0.4% + polyethylene glycol 4000 1.0% + pectin 0.1%. The findings from the intracellular ultrasound images are shown in Figure 10A (real-time findings) and Figure 10a (findings during partial gastric emptying of the contrast agent).

[0095] Round 5 Intracellular Sample 2: Colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IA 0.4% + polyethylene glycol 6000 1.0% + pectin 0.1%. The findings from the intracellular ultrasound images are shown in Figure 10B (real-time findings) and Figure 10b (findings during partial gastric emptying of the contrast agent).

[0096] Round 5 Intracellular Sample 3: Colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IA 0.4% + polyethylene glycol 8000 1.0% + pectin 0.1%. Findings from intracellular ultrasound images are shown in Figure 10C (real-time findings) and Figure 10c (findings during partial gastric emptying of contrast agent).

[0097] Round 5 Intracellular Sample 4: Colloidal microcrystalline cellulose RC591 1% + magnesium aluminum silicate IA 0.4% + polyethylene glycol 6000 2.0% + pectin 0.1%. The findings from the intracellular ultrasound images are shown in Figure 10D (real-time findings) and Figure 10d (findings during partial gastric emptying of the contrast agent).

[0098] Round 5 Intracellular Sample 5: Colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IA 0.4% + polyethylene glycol 6000 3.0% + pectin 0.1%. The findings from the intracellular ultrasound images are shown in Figure 10E (real-time findings) and Figure 10e (findings during partial gastric emptying of the contrast agent).

[0099] Round 5 Intracellular Sample 6: Colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IA 0.4% + polyethylene glycol 6000 4.0% + pectin 0.1%. The findings from the intracellular ultrasound images are shown in Figure 11A (real-time findings) and Figure 11a (findings during partial gastric emptying of the contrast agent).

[0100] Round 5 Intracellular Sample 7: Colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IA 0.4% + polyethylene glycol 6000 5.0% + pectin 0.1%. Findings from intracellular ultrasound images are shown in Figure 11B (real-time findings) and Figure 11b (findings during partial gastric emptying of contrast agent).

[0101] Round 5 Intracellular Sample 8: Colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IC 0.4% + polyethylene glycol 1500 1.0% + pectin 0.1%. Findings from intracellular ultrasound images are shown in Figure 11C (real-time findings) and Figure 11c (findings during partial gastric emptying of contrast agent).

[0102] Round 5 Intracellular Sample 9: Colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IC 0.4% + polyethylene glycol 4000 1.0% + pectin 0.1%. The findings from the intracellular ultrasound images are shown in Figure 11D (real-time findings) and Figure 11d (findings during partial gastric emptying of the contrast agent).

[0103] Round 5 Intracellular Sample 10: Colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IC 0.5% + polyethylene glycol 6000 1.0% + pectin 0.1%. The findings from the intracellular ultrasound images are shown in Figure 11E (real-time findings) and Figure 11e (findings during partial gastric emptying of the contrast agent).

[0104] Round 5 Intracellular Sample 11: Colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IC 0.5% + polyethylene glycol 8000 1.0% + pectin 0.1%. The findings from the intracellular ultrasound images are shown in Figure 12A (real-time findings) and Figure 12a (findings during partial gastric emptying of the contrast agent).

[0105] Round 5 Intracellular Sample 12: Colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IC 0.4% + polyethylene glycol 6000 2.0% + pectin 0.1%. The findings from the intracellular ultrasound images are shown in Figure 12B (real-time findings) and Figure 12b (findings during partial gastric emptying of the contrast agent).

[0106] Round 5 Intracellular Sample 13: Colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IC 0.4% + polyethylene glycol 6000 3.0% + pectin 0.1%. Findings from intracellular ultrasound images are shown in Figure 12C (real-time findings) and Figure 12c (findings during partial gastric emptying of contrast agent).

[0107] Round 5 Intracellular Sample 14: Colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IC 0.4% + polyethylene glycol 6000 4.0% + pectin 0.1%. The findings from the intracellular ultrasound images are shown in Figure 12D (real-time findings) and Figure 12d (findings during partial gastric emptying of the contrast agent).

[0108] Round 5 Intracellular Sample 15: Colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IC 0.4% + polyethylene glycol 6000 5.0% + pectin 0.1%. The findings from the intracellular ultrasound images are shown in Figure 12E (real-time findings) and Figure 12e (findings during partial gastric emptying of the contrast agent).

[0109] In the fifth round of in-vivo screening experiments, the real-time image quality score for all samples was 10 points (with virtually no deductions for roughness or air bubbles), the gastric emptying time of the contrast agent was approximately 20 minutes, and in all samples, the bright spot phenomenon did not appear until the gastric ultrasound contrast agent was completely emptied from the stomach. The results of the fifth round of screening experiments showed that polyethylene glycol can improve real-time images by acting as an antifoamer, and that the bright spot phenomenon can be successfully resolved by compounding it with magnesium aluminum silicate IC or IA. The effect of polyethylene glycol type and concentration was small, which is consistent with previous results.

[0110] Example 3

[0111] 1. Mixing

[0112] Microcrystalline cellulose PH102(D 50 The mass fractions are 4.0% for (100 μm), 0.75% for colloidal microcrystalline cellulose Avicel RC591, 0.75% for magnesium aluminum silicate IC, 0.02% for pectin, 1.0% for polyethylene glycol 6000, 0.1% for potassium sorbate, 0.02% for sucralose, 0.5% for cocoa powder, 0.1% for milk flavor essence, 0.2% for simethicone emulsion (30%), and 92.56% for deionized water.

[0113] 2. Preparation method: 1) Weigh the required amount of magnesium aluminum silicate, add an appropriate amount of water (25% of the total water volume), hydrate under conditions of 80°C while stirring at 200 rpm for 1.5 hours, then perform high-shear homogenization for 3 minutes at a homogenization rate of 10,000 rpm using a FLUKA-FA28 high-shear homogenizer, and cool to room temperature before setting aside. 2) Weigh the required amount of microcrystalline cellulose, add an appropriate amount of water (25% of the total water volume), and stir at 200 rpm until uniformly mixed. 3) Weigh out the prescribed amount of PEG6000, add an appropriate amount of water (10% of the total water volume), and dissolve completely at 200 rpm. 4) Weigh the prescribed amount of colloidal microcrystalline cellulose and pectin, add an appropriate amount of water (25% of the total water volume), stir to disperse uniformly, let stand for 20 minutes (until the powder is completely absorbed), and then perform high-shear homogenization at a homogenization rate of 10,000 rpm for 4 minutes. 5) Weigh the required amounts of cocoa powder, potassium sorbate, and sucralose, add an appropriate amount of water (5% of the total water volume) to disperse and dissolve, and then degas for 30 minutes. 6) Add materials 2, 3, and 4 to the magnesium aluminum silicate suspension all at once, and homogenize at a high shear rate of 10,000 rpm for 3 minutes using a high shear homogenizer. Add material 5 and mix uniformly. Finally, add the prescribed amounts of essence, simethicone emulsion, and remaining water, and mix uniformly. 7) Remove air and pack into containers.

[0114] We compared the intracellular and extracellular ultrasound contrast effects performed in Example 3 and Example 1 of the prior art (CN108939097B). An oral gastric ultrasound contrast agent was prepared using the compounding and preparation method described in Example 1 of the prior art as a comparative example, and the effect of removing bright spots in intracellular contrast was mainly compared. The experimental results are shown in Figure 13. Figure 13A shows a comparison of extracellular contrast, with Example 3 on the left and Example 1 of the prior art (CN108939097B) on the right. The contrast agent was immediately injected due to a large amount of bubbles generated by the vigorous vibration, and extracellular ultrasound contrast was performed. At the moment of injection, interference due to a large amount of bubbles was visible in both images, but in Example 3, the ultrasound image had already recovered completely and uniformly within 1 minute. However, in the image of Example 1 of the prior art (CN108939097B), the ultrasound image only recovered completely and uniformly 5 minutes after vigorous vibration. From the ultrasound image displayed on the same screen after 5 minutes, it can be seen that the internal echoes of both extracorporeal contrast-enhanced images are uniform and consistent (see Figure 13A). The ultrasound image shown in B (Example 3) is superior to that of b (Example 1 of the prior art CN108939097B), with a more uniform internal echo, fewer air bubbles attached to the stomach wall, and a clearer image of the stomach wall. As the observation time progressed, in C (Example 3), the ultrasound image remained uniform until the halfway point of gastric emptying, and no bright spots were observed. However, in c (Example 1 of the prior art CN108939097B), the ultrasound image gradually deteriorated, and interference from many bright spots appeared, significantly affecting the display of the stomach wall.

[0115] When we compared the intracellular and extracellular contrast effects of Example 3 with a commercially available product (Beijing Zhongdao Aode Medical Technology Co., Ltd., Dongbeide brand, oral gastric ultrasound contrast agent), we found that the image effect of Example 3 was slightly superior to that of the commercially available product, as shown in Figure 14. At the same time, when we used the 5-stage 9-plane method of gastric ultrasound (Inventors Liu Zhijun, Standardized Gastric Ultrasound Scanning Planes with Normal Anatomical Variability. Ultraschall Med. 2020 Jun;41(3):318-322.) to scan the gastric fundus, gastric body, gastric angle, gastric sinus long axis, short axis, and coronal plane, we found that after oral administration of the formulation of Example 3, each part of the stomach could be clearly scanned with gastric ultrasound, as shown in Figure 15.

[0116] Example 4

[0117] 1. Mixing

[0118] Microcrystalline cellulose PH102(D 50 The mass fractions are set to 8.0% for 100 μm, 0.75% for colloidal microcrystalline cellulose Avicel RC-591, 0.25% for magnesium aluminum silicate IC, 0.05% for pectin, 1.0% for polyethylene glycol 6000, 0.1% for potassium sorbate, 0.05% for citric acid, 0.03% for sucralose, 0.6% for cocoa powder, 0.1% for milk flavor essence, 0.2% for simethicone emulsion (30%), and 88.87% for deionized water.

[0119] 2. Preparation method: The same preparation method as described in Example 3, Section 2.

[0120] The real-time gastric ultrasound contrast effect after oral administration of the embodiment and the gastric ultrasound contrast effect at the halfway point of gastric emptying are shown in Figures 16A and 16a.

[0121] Example 5

[0122] 1. Mixing

[0123] Microcrystalline cellulose PH102(D 50 The mass fractions are set to 10.0% for (100 μm), 0.4% for colloidal microcrystalline cellulose Avicel RC-591, 0.4% for magnesium aluminum silicate IB, 0.05% for pectin, 1.0% for polyethylene glycol 4000, 0.1% for potassium sorbate, 0.05% for citric acid, 0.03% for sucralose, 0.1% for orange flavor essence, 0.2% for simethicone emulsion (30%), and 87.67% for deionized water.

[0124] 2. Preparation method: The same preparation method as described in Example 3, Section 2.

[0125] The real-time gastric ultrasound contrast effect after oral administration of the embodiment and the gastric ultrasound contrast effect at the halfway point of gastric emptying are shown in Figures 16B and 16b.

[0126] Example 6

[0127] 1. Mixing

[0128] Silicified microcrystalline cellulose (D 50 The mass fractions are set to 8.0% for 80 μm crystalline cellulose, 0.5% for colloidal microcrystalline cellulose Avicel CL-611, 0.3% for magnesium aluminum silicate IA, 0.05% for pectin, 1.0% for polyethylene glycol 6000, 0.1% for sodium benzoate, 0.05% for citric acid, 0.03% for sucralose, 0.6% for cocoa powder, 0.1% for chocolate essence, 0.2% for simethicone emulsion (30%), and 89.07% for deionized water.

[0129] 2. Preparation method: The same preparation method as described in Example 3, Section 2.

[0130] The real-time gastric ultrasound contrast effect after oral administration of the embodiment and the gastric ultrasound contrast effect at the halfway point of gastric emptying are shown in Figures 16C and 16c.

[0131] Example 7

[0132] 1. Mixing

[0133] Microcrystalline cellulose (D 50 The mass fractions are set to 9.0% for 70 μm cellulose, 0.8% for colloidal microcrystalline cellulose Avicel CL-591, 0.2% for magnesium aluminum silicate IA, 0.1% for pectin, 1.0% for polyethylene glycol 4000, 0.1% for sodium benzoate, 0.05% for citric acid, 0.03% for sucralose, 0.6% for matcha powder, 0.1% for matcha essence, 0.2% for simethicone emulsion (30%), and 87.82% for deionized water.

[0134] 2. Preparation method: The same preparation method as described in Example 3, Section 2.

[0135] The real-time gastric ultrasound contrast effect after oral administration of the embodiment and the gastric ultrasound contrast effect at the halfway point of gastric emptying are shown in Figures 16D and 16d.

[0136] Example 8

[0137] 1. Mixing

[0138] Microcrystalline cellulose PH102(D 50The mass fractions are set to 8.0% for (100 μm), 0.3% for colloidal microcrystalline cellulose Avicel RC-591, 0.2% for magnesium aluminum silicate IC, 0.1% for pectin, 1.0% for polyethylene glycol 6000, 0.1% for potassium sorbate, 0.05% for citric acid, 0.03% for sucralose, 0.5% for cocoa powder, 0.1% for chocolate essence, 0.1% for simethicone emulsion, and 89.52% for deionized water.

[0139] 2. Preparation method: The same preparation method as described in Example 3, Section 2.

[0140] The real-time gastric ultrasound contrast effect after oral administration of the embodiment and the gastric ultrasound contrast effect at the halfway point of gastric emptying are shown in Figures 17A and 17a.

[0141] Example 9

[0142] 1. Mixing

[0143] Microcrystalline cellulose PH102(D 50 The mass fractions are set to 10.0% for (100 μm), 0.4% for colloidal microcrystalline cellulose Avicel RC-591, 0.2% for magnesium aluminum silicate IB, 0.1% for pectin, 1.0% for polyethylene glycol 4000, 0.1% for potassium sorbate, 0.05% for citric acid, 0.03% for sodium saccharin, 0.1% for orange flavor essence, 0.2% for simethicone emulsion, and 87.82% for deionized water.

[0144] 2. Preparation method: The same preparation method as described in Example 3, Section 2.

[0145] The real-time gastric ultrasound contrast effect after oral administration of the embodiment and the gastric ultrasound contrast effect at the halfway point of gastric emptying are shown in Figures 17B and 17b.

[0146] Example 10

[0147] 1.Formulation

[0148] Microcrystalline cellulose PH102 (D 50 : 100 μm) has a mass fraction of 4.0%, colloidal microcrystalline cellulose Avicel RC591 has a mass fraction of 0.75%, magnesium aluminum silicate IC has a mass fraction of 0.75%, pectin has a mass fraction of 0.02%, polyethylene glycol 6000 has a mass fraction of 1.0%, potassium sorbate has a mass fraction of 0.1%, sucralose has a mass fraction of 0.02%, cocoa powder has a mass fraction of 0.5%, milk flavor essence has a mass fraction of 0.1%, and deionized water has a mass fraction of 92.76%.

[0149] 2.Preparation method: the same as the preparation method described in 2 of Example 3.

[0150] The real-time gastric ultrasonic contrast effect and the gastric ultrasonic contrast effect at the half gastric emptying time point after oral administration of this example are as shown in Figure 17C and Figure 17c.

[0151] Example 11

[0152] 1.Formulation

[0153] Microcrystalline cellulose PH102 (D 50 : 100 μm) has a mass fraction of 7.0%, colloidal microcrystalline cellulose Avicel RC-591 has a mass fraction of 0.5%, magnesium aluminum silicate IC has a mass fraction of 0.25%, pectin has a mass fraction of 0.1%, polyethylene glycol 6000 has a mass fraction of 1.0%, potassium sorbate has a mass fraction of 0.1%, citric acid has a mass fraction of 0.05%, sucralose has a mass fraction of 0.03%, cocoa powder has a mass fraction of 0.6%, milk flavor essence has a mass fraction of 0.1%, and deionized water has a mass fraction of 90.27%.

[0154] 2. Preparation method: The same preparation method as described in Example 3, Section 2.

[0155] The real-time gastric ultrasound contrast effect after oral administration of the embodiment and the gastric ultrasound contrast effect at the halfway point of gastric emptying are shown in Figures 17D and 17d.

[0156] Example 12

[0157] 1. Mixing

[0158] Microcrystalline cellulose PH102(D 50 The mass fractions are set to 9.0% for 100 μm particles, 0.4% for colloidal microcrystalline cellulose Avicel RC-591, 0.35% for magnesium aluminum silicate IC, 0.1% for pectin, 1.0% for polyethylene glycol 4000, 0.1% for potassium sorbate, 0.05% for citric acid, 0.03% for sucralose, 0.4% for cocoa powder, and 88.57% for deionized water.

[0159] 2. Preparation method: The same preparation method as described in Example 3, Section 2.

[0160] The real-time gastric ultrasound contrast effect after oral administration of the embodiment and the gastric ultrasound contrast effect at the halfway point of gastric emptying are shown in Figures 18A and 18a.

[0161] Example 13

[0162] 1. Mixing

[0163] Silicified microcrystalline cellulose (D 50The mass fractions are set to 9.0% for 80 μm (80 μm), 0.4% for colloidal microcrystalline cellulose Avicel CL-611, 0.3% for magnesium aluminum silicate IB, 0.05% for pectin, 1.0% for polyethylene glycol 6000, 0.1% for sodium benzoate, 0.05% for citric acid, 0.03% for sucralose, 0.6% for cocoa powder, 0.2% for simethicone emulsion, 0.1% for chocolate essence, and 89.27% ​​for deionized water.

[0164] 2. Preparation method: The same preparation method as described in Example 3, Section 2.

[0165] The real-time gastric ultrasound contrast effect after oral administration of the embodiment and the gastric ultrasound contrast effect at the halfway point of gastric emptying are shown in Figures 18B and 18b.

[0166] Example 14

[0167] 1. Mixing

[0168] Microcrystalline cellulose (D 50 The mass fractions are set to 10.0% for 70 μm, 0.3% for colloidal microcrystalline cellulose Avicel CL-611, 0.4% for magnesium aluminum silicate IA, 0.1% for pectin, 1.0% for polyethylene glycol 6000, 0.1% for potassium sorbate, 0.05% for citric acid, 0.03% for sucralose, 0.6% for matcha powder, 0.1% for matcha essence, and 87.32% for deionized water.

[0169] 2. Preparation method: The same preparation method as described in Example 3, Section 2.

[0170] The real-time gastric ultrasound contrast effect after oral administration of the embodiment and the gastric ultrasound contrast effect at the halfway point of gastric emptying are shown in Figures 18C and 18c.

[0171] Example 15

[0172] 1. Mixing

[0173] Microcrystalline cellulose PH102(D 50 The mass fractions are set as follows: 8.0% for 100 μm particles, 0.35% for colloidal microcrystalline cellulose Avicel CL-611, 0.25% for magnesium aluminum silicate IC, 0.1% for pectin, 1.0% for polyethylene glycol 6000, 0.1% for potassium sorbate, 0.05% for citric acid, 0.03% for sucralose, 0.5% for cocoa powder, and 89.52% for deionized water.

[0174] 2. Preparation method: The same preparation method as described in Example 3, Section 2.

[0175] The real-time gastric ultrasound contrast effect after oral administration of the embodiment and the gastric ultrasound contrast effect at the halfway point of gastric emptying are shown in Figures 18D and 18d.

[0176] Example 16

[0177] 1. Mixing

[0178] Microcrystalline cellulose (D 50 The mass fractions are set to 7.0% for (70 μm), 0.3% for colloidal microcrystalline cellulose Avicel CL-611, 0.2% for magnesium aluminum silicate IB, 0.1% for pectin, 1.0% for polyethylene glycol 4000, 0.1% for potassium sorbate, 0.05% for citric acid, 0.03% for sodium saccharin, 0.5% for matcha powder, and 90.72% for deionized water.

[0179] 2. Preparation method: The same preparation method as described in Example 3, Section 2.

[0180] The real-time gastric ultrasound contrast effect after oral administration of the embodiment and the gastric ultrasound contrast effect at the halfway point of gastric emptying are shown in Figures 19A and 19a.

[0181] Example 17

[0182] 1. Mixing

[0183] Microcrystalline cellulose PH102(D 50 The mass fractions are set as follows: 8.0% for 100 μm particles, 0.25% for colloidal microcrystalline cellulose Avicel RC-591, 0.35% for magnesium aluminum silicate IA, 0.05% for pectin, 1.0% for polyethylene glycol 6000, 0.1% for potassium sorbate, 0.05% for citric acid, 0.02% for sucralose, 0.5% for matcha powder, and 89.68% for deionized water.

[0184] 2. Preparation method: The same preparation method as described in Example 3, Section 2.

[0185] The real-time gastric ultrasound contrast effect after oral administration of the embodiment and the gastric ultrasound contrast effect at the halfway point of gastric emptying are shown in Figures 19B and 19b.

[0186] Example 18

[0187] 1. Mixing

[0188] Silicified microcrystalline cellulose (D 50 The mass fractions are set to 8.0% for (100 μm), 0.35% for colloidal microcrystalline cellulose Avicel RC-591, 0.35% for magnesium aluminum silicate IC, 0.05% for pectin, 1.0% for polyethylene glycol 4000, 0.1% for potassium sorbate, 0.05% for citric acid, 0.03% for sucralose, 0.5% for cocoa powder, and 89.57% for deionized water.

[0189] 2. Preparation method: The same preparation method as described in Example 3, Section 2.

[0190] The real-time gastric ultrasound contrast effect after oral administration of the embodiment and the gastric ultrasound contrast effect at the halfway point of gastric emptying are shown in Figures 19C and 19c.

[0191] Example 19

[0192] 1. Mixing

[0193] Microcrystalline cellulose PH102(D 50 The mass fractions are set to 8.0% for 100 μm particles, 0.35% for colloidal microcrystalline cellulose Avicel RC-591, 0.15% for magnesium aluminum silicate IA, 0.15% for pectin, 1.0% for polyethylene glycol 6000, 0.1% for potassium sorbate, 0.05% for citric acid, 0.02% for sucralose, 0.5% for cocoa powder, 0.1% for chocolate essence, and 89.58% for deionized water.

[0194] 2. Preparation method: The same preparation method as described in Example 3, Section 2.

[0195] The real-time gastric ultrasound contrast effect after oral administration of the embodiment and the gastric ultrasound contrast effect at the halfway point of gastric emptying are shown in Figures 19D and 19d.

[0196] The specific clinical application method of the present invention is as follows. The prepared ready-to-use oral gastric ultrasound contrast agent (300 mL) is placed in a 650 mL package bottle. Before use, the bottle cap is opened, 300 mL of drinking water is added (drinking water at the patient's preferred temperature may be added), the final volume is adjusted to the 600 mL mark, and the bottle is shaken up and down for 5-10 seconds to mix evenly. The patient can drink it directly orally. By ingesting approximately 500 mL of this contrast solution (this amount can be increased or decreased depending on the patient's stomach volume), the gastric cavity is filled, gas interference in the stomach is eliminated, the structure of the stomach wall is clearly visualized, and the clinical requirements of gastric ultrasound examination are met.

[0197] The most important components in the formulation of this invention are a compound formulation of magnesium aluminum silicate, colloidal microcrystalline cellulose, and pectin, and microcrystalline cellulose or silicified microcrystalline cellulose. By using a compound formulation of magnesium aluminum silicate, colloidal microcrystalline cellulose, and pectin, this invention maintains excellent thixotropy and stability, and preserves the product's characteristics of being ready for immediate use, making it very convenient for clinical use. More importantly, by using a compound formulation of magnesium aluminum silicate and colloidal microcrystalline cellulose, the bright spot phenomenon that is prone to occur in intracellular contrast imaging with conventional products (CN108939097B) is eliminated, and polyethylene glycol improves real-time image quality as an antifoaming agent, thus ensuring the excellent ultrasound contrast quality of the contrast agent and guaranteeing its clinical application.

Claims

1. A ready-to-use liquid oral gastric ultrasound contrast agent, characterized in that magnesium aluminum silicate is added as a compound thickening and suspension aid during formulation.

2. The ultrasound contrast agent according to claim 1, characterized in that the compound thickening suspension aid further comprises colloidal cellulose and pectin.

3. The ultrasound contrast agent according to claim 1 or 2, characterized in that the contrast agent is used in the preparation of a gastric ultrasound contrast agent.

4. A ready-to-use liquid oral gastric ultrasound contrast agent, characterized in that it comprises a compound thickening suspension aid, ultrasound contrast-enhancing particulate matter, an antifoaming agent, a flavoring agent, a preservative, and water.

5. The ultrasound contrast agent according to claim 4, characterized in that the compound thickening suspension aid comprises magnesium aluminum silicate, colloidal cellulose, and pectin.

6. The ultrasound contrast agent according to claim 4, characterized in that the defoaming agent is one or a combination of several of polyethylene glycol, simethicone, and simethicone emulsion.

7. The ultrasound contrast agent according to claim 4, characterized in that it is used in the preparation of gastric ultrasound contrast agents.

8. In a method for preparing a ready-to-use liquid oral gastric ultrasound contrast agent according to any one of claims 4 to 6, specifically, (1) Weigh the required amount of magnesium aluminum silicate, add an appropriate amount of water, stir at 80°C to hydrate, then homogenize, and cool to room temperature. (2) Weigh the required amount of microcrystalline cellulose, add an appropriate amount of water, stir to mix uniformly, and degas the mixture. (3) The steps of weighing the prescribed amount of polyethylene glycol and adding an appropriate amount of water to dissolve it completely, (4) Weighing the prescribed amount of colloidal microcrystalline cellulose and pectin, adding an appropriate amount of water, stirring to disperse uniformly, and then letting it stand to homogenize, (5) The steps include weighing out the flavoring agents, preservatives and other additives in the prescribed amount, adding an appropriate amount of water to disperse and dissolve them, and then degassing the mixture. (6) Add the materials from steps (2), (3), and (4) in order to the magnesium aluminum silicate suspension obtained in (1), homogenize, then add the material from (5) and stir uniformly, and then add the prescribed amount of essence, the remaining water, etc., and stir uniformly. (7) The step of degassing and packing into a container, is characterized by including A method for preparing a ready-to-use liquid oral gastric ultrasound contrast agent according to any one of claims 4 to 6.

9. Application of the contrast agent obtained by the preparation method described in claim 8 to the preparation of gastric ultrasound contrast agent.

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