Ready-to-use liquid oral gastric ultrasound contrast agent formula based on magnesium aluminum silicate and microcrystalline cellulose, and manufacturing method

Abstract

A ready-to-use liquid oral gastric ultrasound contrast agent formula based on magnesium aluminum silicate and microcrystalline cellulose, and a manufacturing method, relating to the technical field of medical ultrasound diagnostic reagents. Magnesium aluminum silicate and materials such as microcrystalline cellulose, silicified microcrystalline cellulose, colloidal microcrystalline cellulose, polyethylene glycol, and xylitol were screened for compounding, and by means of in vitro ultrasound imaging and in vivo ultrasound imaging, it was finally determined to select magnesium aluminum silicate, colloidal microcrystalline cellulose, and pectin for compounding, which not only has an excellent suspending effect, but also can eliminate the phenomenon of false echogenic masses in in vivo imaging, and polyethylene glycol as a defoaming agent improves instant image quality. The forgoing ultrasound imaging agent formula maintains excellent thixotropy and stability and excellent ultrasound imaging quality while continuing the ready-to-use feature of the product, providing great convenience in clinical use.

Description

A formula and preparation method of a ready-to-use liquid oral gastric ultrasound contrast agent based on magnesium aluminum silicate and microcrystalline cellulose Technical Field

[0001] The present invention belongs to the technical field of medical ultrasonic diagnostic reagents, and in particular relates to a formula and a preparation method of a ready-to-use liquid oral gastric ultrasonic developer based on magnesium aluminum silicate and microcrystalline cellulose. Background Art

[0002] The technical problem to be solved by the present invention is to address the shortcomings of the original invention (authorization publication number: CN108939097B). Using CN108939097B as a reference patent, the present invention provides a formula for a ready-to-use oral gastric ultrasound contrast agent and its preparation method to achieve optimal in vivo imaging quality. During in vivo imaging with the original invention (authorization publication number: CN108939097B), the contrast agent in the subject's stomach may gradually develop a "light cluster" phenomenon (appearing as a high-echoic mass under ultrasound) over time. This "light cluster" phenomenon can affect gastric ultrasound observation, causing uneven echoes within the contrast agent and attenuating the posterior echo, which in turn affects observation of the stomach wall and ultimately compromises the effectiveness of gastric ultrasound examinations. During in vivo imaging, the presence of these "light blobs" varies from individual to individual, and their impact on ultrasound imaging ranges from mild to severe, sometimes even making it difficult to continue the gastric ultrasound examination. Addressing these "light blobs" is essential and crucial to improving the stability of gastric ultrasound imaging and minimizing the impact of individual variability. Analysis of these light blobs may be related to factors such as intragastric fluid, mucus and small bubbles in the fluid, air bubbles introduced during oral swallowing, contrast agent aggregation, and gastric peristalsis to empty the contrast agent.

[0003] Summary of the Invention

[0004] In view of the defects of the existing technology, the present invention mainly provides a formula and preparation method of a ready-to-use liquid oral gastric ultrasound contrast agent based on magnesium aluminum silicate and microcrystalline cellulose.

[0005] In order to achieve the above-mentioned purpose of the invention, the technical solution adopted by the present invention is as follows.

[0006] The present invention provides a ready-to-use liquid oral gastric ultrasound developer, characterized in that magnesium aluminum silicate is added to the developer formula as a composite suspending and thickening agent.

[0007] Furthermore, the compound suspending thickener also includes colloidal cellulose and pectin.

[0008] Furthermore, the developer is used in the preparation of a stomach ultrasound developer.

[0009] The present invention also provides a ready-to-use liquid oral gastric ultrasound developer, characterized in that the developer consists of a compounded suspending thickener, ultrasound imaging particulate matter, a defoaming agent, a flavoring agent, a preservative and water.

[0010] Furthermore, the compound suspending thickener consists of magnesium aluminum silicate, colloidal cellulose and pectin.

[0011] Furthermore, the dosage (w / w) of the magnesium aluminum silicate is in the range of 0.01 to 3.0%, with a preferred range of 0.05 to 1.0%, so as to obtain the best gastric ultrasound imaging effect; the magnesium aluminum silicate models used in the formula are IA, IB, IC, IIA (classification models of the 2020 edition of the "Chinese Pharmacopoeia"), and a mixture of any two or more of them; among which the preferred magnesium aluminum silicate models are IA and IC.

[0012] The amount (w / w) of the colloidal cellulose is in the range of 0.01 to 3.0%, preferably in the range of 0.05 to 1.0%, so as to obtain the best gastric ultrasound imaging effect; the colloidal cellulose used is Avicel RC-501, Avicel RC-581, Avicel RC-591, Avicel CL-611, and a mixture of any two or more thereof; Avicel RC-591 and Avicel CL-611 are preferred.

[0013] The dosage (w / w) of the pectin is in the range of 0.01 to 1.0%, preferably in the range of 0.05 to 0.5%, so as to obtain the best stomach ultrasound imaging effect.

[0014] Furthermore, the defoaming agent is one or a combination of polyethylene glycol, simethicone and simethicone emulsion.

[0015] Furthermore, the ultrasonic imaging particulate material is microcrystalline cellulose or silicified microcrystalline cellulose; the microcrystalline cellulose is a high-echo particulate material with a particle size (D50) of 20 to 150 μm, preferably microcrystalline cellulose with a particle size (D50) of 50 to 110 μm; the amount of microcrystalline cellulose used (w / w) is 1 to 20%, preferably 2 to 10%.

[0016] Furthermore, the developer is used in the preparation of a stomach ultrasound developer.

[0017] The present invention also provides a method for preparing any of the above-mentioned ready-to-use liquid oral gastric ultrasound contrast agents, characterized in that the specific steps include:

[0018] (1) Weigh the formulated amount of magnesium aluminum silicate, add an appropriate amount of water, stir and hydrate at 80°C, and then homogenize; cool to room temperature and set aside;

[0019] (2) Weigh the formulated amount of microcrystalline cellulose, add appropriate amount of water, stir and mix, and degas;

[0020] (3) Weigh the prescribed amount of polyethylene glycol and add an appropriate amount of water until it is completely dissolved;

[0021] (4) Weigh the prescribed amount of colloidal microcrystalline cellulose and pectin, add appropriate amount of water, stir to disperse evenly, and let stand until homogenized;

[0022] (5) Weigh the formulated amount of flavoring agents, preservatives and other additives, add appropriate amount of water to disperse and dissolve, and degas;

[0023] (6) Add the materials in steps (2), (3), and (4) to the aluminum magnesium silicate suspension prepared in step (1) at once, homogenize, then add the material in step (5) and stir evenly; then add the formulated amount of flavoring, the remaining amount of water, etc., and stir evenly;

[0024] (7) Degassing and filling.

[0025] Furthermore, the developer prepared by the preparation method is used in the preparation of gastric ultrasound developer.

[0026] The compound suspending thickener of the present invention can not only maintain the suspension uniformity of the ready-to-use oral gastric ultrasound contrast agent during storage and the easy dilution after adding water; more importantly, it can eliminate the "light cluster" phenomenon in the image during in vivo imaging, greatly increase the image clarity, and improve the accuracy of diagnosis.

[0027] Compared with the prior art, the present invention has the following advantages and beneficial effects.

[0028] (1) The applicant first used a combination of magnesium aluminum silicate and colloidal microcrystalline cellulose, eliminating the phenomenon of light clusters that are prone to appear in in vivo imaging of the prior art product (CN108939097B), and significantly extending the imaging observation time.

[0029] (2) The formula of the ultrasonic imaging agent disclosed in the present invention can shorten the time for the ultrasonic image to recover to the ideal state after violent shaking to less than 1 minute, so as to better eliminate the influence of bubbles on the ultrasonic image and better meet the ultrasonic imaging requirements during clinical examinations.

[0030] (3) The ultrasound imaging agent disclosed in the present invention maintains excellent thixotropy and excellent stability while continuing the ready-to-use feature of the product, providing great convenience in clinical use.

[0031] (4) In addition to the aforementioned significant advantages, the instant oral gastric ultrasound contrast agent disclosed in the present invention also fully retains the advantages of the prior art (CN108939097B), such as high safety, no toxic side effects, uniform particle distribution, long shelf life, good taste, easy oral administration, convenient brewing and use, the ability to quickly eliminate small bubbles and mucus interference attached to the stomach wall, and cost control. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 Ultrasound images from an in vitro imaging screening experiment. A: After vigorous shaking, numerous bubbles are visible within the developer, resulting in uneven echogenicity. B: The bubbles dissipate over time, gradually reducing the internal bubble interference. D: The bubbles completely dissipate, and the echogenicity within the developer returns to uniformity. The time from vigorous shaking to the ultrasound image in Figure D is recorded as the time it takes for the image to return to its ideal state after vigorous shaking.

[0033] Figure 2. Impact of light masses on ultrasound images. A: Immediate ultrasound image after oral contrast administration (score 10): uniform internal echogenicity. However, a small amount of light masses may be observed 20 minutes later, resulting in mild imaging impact. B: Immediate ultrasound image (score 10): uniform internal echogenicity. However, b: moderate amount of light masses may be observed 20 minutes later, resulting in moderate imaging impact. C: Immediate ultrasound image (score 10): uniform internal echogenicity. However, a large amount of light masses may be observed 30 minutes later, resulting in severe imaging impact.

[0034] Figure 3. Impact of light clusters on ultrasound images in the first round of samples. A: Immediate ultrasound image after oral contrast administration (score 10): uniform internal echogenicity. However, 20 minutes later, a small amount of light clusters were visible, with minimal impact on imaging. B: Immediate ultrasound image (score 10): uniform internal echogenicity. However, 20 minutes later, a small amount of light clusters were visible, with minimal impact on imaging. C: Immediate ultrasound image (score 10): uniform internal echogenicity. 20 minutes later, examination showed virtually no light clusters, with minimal impact on imaging.

[0035] Figure 4. Impact of sample light clumps on ultrasound images during the first round of testing. A. Immediate ultrasound image after oral contrast administration (score 10): uniform internal echogenicity. However, 20 minutes later, a small amount of light clumps were visible, with minimal imaging impact. B. Immediate ultrasound image (score 10): uniform internal echogenicity. However, 20 minutes later, a small amount of light clumps were visible, with minimal imaging impact. C. Immediate ultrasound image (score 10): uniform internal echogenicity. However, 20 minutes later, a small amount of light clumps were visible, with minimal imaging impact.

[0036] Figure 5. Ultrasound images of the second round of samples after compounding with polyethylene glycol. The left image, ABCDEF, shows an immediate ultrasound image 10 minutes after oral contrast administration, showing uniform internal echoes. However, the right image, abcdef, shows a small amount of light clusters still visible 20 minutes later, slightly affecting the imaging.

[0037] Figure 6. Ultrasound findings from the third round of sample analysis. The left image, ABCDEF, shows an immediate ultrasound image taken with oral contrast agent at 10 minutes, showing uniform internal echoes. However, the right image, ABCDEF, shows a small amount of light clusters visible 20 minutes later, slightly affecting the imaging.

[0038] Figure 7. Ultrasound findings from the third round of sample analysis. The left image, ABCDEF, shows an immediate ultrasound image taken with oral contrast agent at 10 minutes, showing uniform internal echoes. However, the right image, abcdef, shows a small amount of light clusters still visible 20 minutes later, slightly affecting the imaging.

[0039] Figure 8. Ultrasound findings from the third round of sample analysis. The left image, ABCDEF, shows an immediate ultrasound image taken with oral contrast agent at 10 minutes, showing uniform internal echoes. However, the right image, ABCDEF, shows a small amount of light clusters visible 20 minutes later, slightly affecting the imaging.

[0040] Figure 9: Ultrasound findings from the fourth round of the sample. Images ABCD on the left show an immediate ultrasound image at 10 minutes after oral contrast agent administration. The internal echoes are more uniform and delicate, and the stomach wall is more clearly visible. Images ABCD on the right show no internal light masses until the stomach is half empty, which has no effect on imaging.

[0041] Figure 10: Ultrasound findings from the fifth round of the sample. The left image (ABCDE) shows an immediate ultrasound image at 10 minutes after oral contrast administration. The internal echoes are more uniform and delicate, and the stomach wall is more clearly visible. The right image (ABCDE) shows no internal light masses until the stomach is half empty, which has no effect on imaging.

[0042] Figure 11: Ultrasound findings from the fifth round of the sample. The left image (ABCDE) shows an immediate ultrasound image at 10 minutes after oral contrast administration. The internal echoes are more uniform and delicate, and the stomach wall is more clearly visible. The right image (ABCDE) shows no internal light masses until the stomach is half empty, which has no effect on imaging.

[0043] Figure 12: Ultrasound findings from the fifth round of the sample. The left image (ABCDE) shows an immediate ultrasound image at 10 minutes after oral contrast administration. The internal echoes are more uniform and delicate, and the stomach wall is more clearly visible. The right image (ABCDE) shows no internal light masses until the stomach is half empty, which has no effect on imaging.

[0044] Figure 13 shows a comparison of the ultrasound in-vivo and out-vivo imaging effects of Example 3 and Example 1 in the prior art (CN108939097B). A shows a comparison of in-vitro imaging, with Example 3 on the left and Example 1 in the prior art (CN108939097B) on the right. After 5 minutes of vigorous shaking, the ultrasound shows that the internal echoes of both in-vitro imaging are uniform. B (Example 3) shows that the ultrasound image is better than b (Example 1 in the prior art CN108939097B). B has more uniform internal echoes, fewer wall bubbles, and a clearer display of the stomach wall. As the observation time passes, C (Example 3) shows that the ultrasound image remains uniform until the gastric half-emptying time, with no light clusters appearing; however, c (Example 1 in the prior art CN108939097B) shows that the ultrasound image is getting worse and worse, and even a lot of light cluster interference appears, which seriously affects the display of the stomach wall.

[0045] Figure 14 compares the ultrasound in-vivo and out-vivo imaging effects of Example 3 (left side) and the commercially available product (right side). A. Comparison of in-vitro imaging: the left side of Figure A is Example 3, and the right side of Figure A is the commercially available product. The internal echoes of both are uniform. B. Comparison of short-axis ultrasound images of the gastric body b (commercially available product). C. Comparison of ultrasound images of the oblique section of the gastric fundus c (commercially available product). D. Comparison of ultrasound images of the coronal plane of the gastric angle. E. Comparison of ultrasound images of the coronal plane of the gastric angle d (commercially available product). 20 minutes after the examination, the instantaneous ultrasound images of both were 10 points, and the internal echoes were uniform. However, the posterior echo attenuation of the left image (Example 3) was slightly smaller than that of the right image (commercially available product), and the gastric wall was displayed more clearly. Both were not affected by light clusters during the entire examination process.

[0046] FIG15 : After a volunteer orally took the example, the five-step nine-plane method of gastric ultrasound was used to completely scan the long axis, short axis and coronal plane of the gastric fundus, gastric body, gastric angle and gastric antrum.

[0047] Figure 16 shows the in vivo gastric ultrasound imaging results of Examples 4 to 7. Images A (Example 4), B (Example 5), C (Example 6), and D (Example 7) on the left show gastric ultrasound images 10 minutes after oral administration, showing uniform and delicate echoes inside and a clear view of the stomach wall. Images a (Example 4), b (Example 5), c (Example 6), and d (Example 7) on the right show images taken until the time of half-emptying of the stomach. The stomach ultrasound shows no light masses inside the contrast agent, which has no effect on imaging, and a clear view of the stomach wall.

[0048] Figure 17 shows the in vivo gastric ultrasound imaging results of Examples 8 to 11. Images A (Example 8), B (Example 9), C (Example 10), and D (Example 11) on the left show gastric ultrasound images 10 minutes after oral administration. The internal echoes are uniform and delicate, and the gastric wall is clearly visible. Images a (Example 8), b (Example 9), c (Example 10), and d (Example 11) on the right show images taken until the gastric half-emptying time. The gastric ultrasound images show no light masses within the contrast agent, which have no effect on imaging, and the gastric wall is clearly visible.

[0049] Figure 18 shows the in vivo gastric ultrasound imaging results of Examples 12 to 15. Images A (Example 12), B (Example 13), C (Example 14), and D (Example 15) on the left show gastric ultrasound images 10 minutes after oral administration, showing uniform and delicate echoes inside and a clear view of the stomach wall. Images a (Example 12), b (Example 13), c (Example 14), and d (Example 15) on the right show images taken until the time of half-emptying of the stomach. The stomach ultrasound shows no light masses inside the contrast agent, which has no effect on imaging, and a clear view of the stomach wall.

[0050] Figure 19 shows the in vivo gastric ultrasound imaging results of Examples 16 to 20. Images A (Example 16), B (Example 17), C (Example 18), and D (Example 19) on the left show gastric ultrasound images 10 minutes after oral administration, showing uniform and delicate internal echoes and clear visualization of the gastric wall. Images a (Example 16), b (Example 17), c (Example 18), and d (Example 19) on the right show images taken until the gastric half-emptying time. The gastric ultrasound images show no light masses within the contrast agent, which have no effect on imaging, and the gastric wall is clearly visualized. DETAILED DESCRIPTION

[0051] The present invention will be further described in detail below by means of specific examples and accompanying drawings. The following examples are only provided to further illustrate the present invention and should not be construed as limiting the present invention.

[0052] Example 1.

[0053] Using CN108939097B as a reference for comparative research, the applicant first conducted an in vitro ultrasound imaging screening experiment. The evaluation indicators mainly included: 1) the immediate in vitro ultrasound imaging score after conventional brewing; 2) the time it takes for the ultrasound image to recover to a uniform echo and be unaffected by bubbles after violently shaking the bottle to create a large number of bubbles. This experiment was designed to simulate the adverse effects of bubbles in the developer caused by the human swallowing action on imaging.

[0054] Although the instant in vitro ultrasound imaging score of the CN108939097B comparative patent is basically a full score of 10 points, the time it takes for the ultrasound image to return to the ideal state after violent shaking is greater than ten minutes. Therefore, we optimized the concentration of colloidal microcrystalline cellulose in the CN108939097B patent, and used a new compound material as a suspending agent, which can shorten the interference of bubbles on the ultrasound image after violent shaking 5 times to less than 1 minute to restore the image to the ideal state, thereby better eliminating the impact of bubbles on the ultrasound image and better meeting the ultrasound imaging requirements during clinical examinations. To this end, the applicant conducted an in vitro imaging screening experiment, including the compounding of colloidal microcrystalline cellulose and polyethylene glycol (different molecular weight models), polypropylene glycol, xylitol, fructose, magnesium aluminum silicate, pectin and other materials. The in vitro ultrasound imaging screening experiment process is shown in Figure 1. Results from in vitro ultrasound imaging screening experiments indicate that a combination 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%) can substantially overcome the adverse effects of air bubbles generated by simulated swallowing. Table 1 lists experimental data for eight representative, feasible samples.

[0055] Table 1 In vitro ultrasound imaging experimental data of some samples

[0056] The imaging particulate matter of the eight representative samples listed in Table 1 is 8% (w / w) microcrystalline cellulose PH102, 0.1% by mass of potassium sorbate, 0.05% by mass of citric acid, 0.03% by mass of sucralose, and 0.5% by mass of cocoa powder. The suspending agent composition is as follows:

[0057] Sample in vitro 1: colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IC 0.2% + pectin 0.1%;

[0058] Sample in vitro 2: colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 1500 5.0% + pectin 0.1%;

[0059] Sample in vitro 3: colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 4000 5.0% + pectin 0.1%;

[0060] Sample in vitro 4: colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 5.0% + pectin 0.1%;

[0061] Sample in vitro 5: colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 8000 5.0% + pectin 0.1%;

[0062] Sample in vitro 6: colloidal microcrystalline cellulose RC591 0.5% + polypropylene glycol 4000 5.0% + pectin 0.1%;

[0063] Sample in vitro 7: colloidal microcrystalline cellulose RC591 0.5% + xylitol 4.0% + pectin 0.1%;

[0064] Sample in vitro 8: colloidal microcrystalline cellulose RC591 0.5% + fructose 4.0% + pectin 0.1%.

[0065] Example 2.

[0066] Based on the aforementioned in vitro screening experiments, the applicant conducted a large number of in vivo gastric ultrasound imaging contrast agent formulation screening experiments, including compounding of materials such as microcrystalline cellulose, silicified microcrystalline cellulose and colloidal microcrystalline cellulose, magnesium aluminum silicate, polyethylene glycol, xylitol, fructose, and pectin. The focus was on in vivo gastric ultrasound imaging and the light cluster phenomenon. The in vivo imaging screening evaluation criteria mainly included: 1) immediate image quality score (including deductions for internal echo roughness and mural bubbles); 2) the presence of light clusters, the time of light cluster appearance, and the degree of image impact (mild, moderate, severe); and 3) the gastric half-emptying time of the contrast agent.

[0067] The first round of in vivo imaging screening experiments aimed to address the photomask issue. This preliminary screening of excipients was conducted. The results for some samples with minimal photomask effects are shown in Table 2. Other suboptimal samples, which produced moderate to severe photomask effects, are not listed in this patent application due to space limitations. The in vivo ultrasound findings of samples with mild, moderate, and severe photomask effects on ultrasound images are shown in Figure 2.

[0068] Table 2 In vivo ultrasound imaging experimental data of some samples

[0069] The six representative samples listed in Table 2 (the formula ratio is mass fraction): the imaging particulate matter is 8% microcrystalline cellulose PH102, potassium sorbate is 0.1%, citric acid is 0.05%, sucralose is 0.03%, cocoa powder is 0.5%, and simethicone emulsion (30%) is 0.2%. The composition of the compound suspending agent is as follows.

[0070] First round in vivo sample 1: colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 1500 5.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 3A (immediately) and Figure 3a (after 20 minutes).

[0071] First round in vivo sample 2: colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 4000 5.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 3B (immediately) and Figure 3B (after 20 minutes).

[0072] First round in vivo sample 3: colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 5.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 3C (immediately) and Figure 3C (after 20 minutes).

[0073] First round in vivo sample 4: colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 8000 5.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 4A (immediately) and Figure 4a (after 20 minutes).

[0074] First round in vivo sample 5: colloidal microcrystalline cellulose RC591 0.5% + xylitol 4.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 4B (immediately) and Figure 4B (after 20 minutes).

[0075] First round in vivo sample 6: colloidal microcrystalline cellulose RC591 0.5% + fructose 4.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 4C (immediately) and Figure 4C (after 20 minutes).

[0076] Through the first round of in vivo imaging screening experiments, it was preliminarily found that further reducing the concentration of colloidal microcrystalline cellulose and compounding it with polyethylene glycols, fructose, pectin and other substances can alleviate the photoclusters phenomenon, especially PEG6000, which had the most obvious effect. Therefore, the concentration of PEG6000 was screened, and the second round of in vivo imaging screening experiments was carried out.

[0077] In the second round, samples screened by PEG6000 concentration (formulation ratio is mass fraction): imaging particulate matter is 8% microcrystalline cellulose PH102, potassium sorbate is 0.1%, citric acid is 0.05%, sucralose is 0.03%, cocoa powder is 0.5%, and simethicone emulsion (30%) is 0.2%. The composition of the compound suspending agent and the imaging results are as follows.

[0078] Second round in vivo sample 1: colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 1.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 5A (immediately) and Figure 5a (after 20 minutes).

[0079] Second round in vivo sample 2: colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 2.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 5B (immediately) and Figure 5B (after 20 minutes).

[0080] Second round in vivo sample 3: colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 3.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 5C (immediately) and Figure 5C (after 20 minutes).

[0081] Second round in vivo sample 4: colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 4.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 5D (immediately) and Figure 5D (after 20 minutes).

[0082] Second round in vivo sample 5: colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 5.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 5E (immediately) and Figure 5F (after 20 minutes).

[0083] Second round in vivo sample 6: colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 6.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 5F (immediately) and Figure 5F (after 20 minutes).

[0084] In the second round of in vivo screening, all samples achieved an immediate image quality score of 10, but light swarming was occasionally observed (albeit mildly). The gastric half-emptying time of the contrast agent was approximately 20 minutes, similar to the first round. These results suggest that PEG 6000 concentration is not the primary factor affecting light swarming. Therefore, we conducted a third round of in vivo imaging screening by screening combinations of PEG 6000 and other excipients.

[0085] The third round of compound screening of in vivo samples PEG6000 and other excipients (formulation ratio is mass fraction): the imaging particulate matter is 8% microcrystalline cellulose PH102, 0.1% potassium sorbate, 0.05% citric acid, 0.03% sucralose, 0.5% cocoa powder, 0.2% simethicone emulsion (30%), and the composition of the compound suspending agent and the imaging results are as follows.

[0086] The third round of in vivo sample 1: colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 1.0% + xylitol 2.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 6A (immediately) and Figure 6a (after 20 minutes).

[0087] The third round of in vivo sample 2: colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 1.0% + xylitol 3.0% + pectin 0.1%. The in vivo ultrasound images are shown in Figure 6B (immediately) and Figure 6B (after 20 minutes).

[0088] The third round of in vivo sample 3: colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 1.0% + xylitol 4.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 6C (immediately) and Figure 6C (after 20 minutes).

[0089] The third round of in vivo sample 4: colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 1.0% + xylitol 5.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 6D (immediately) and Figure 6D (after 20 minutes).

[0090] The third round of in vivo sample 5: colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 5.0% + xylitol 2.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 6E (immediately) and Figure 6e (after 20 minutes).

[0091] The third round of in vivo sample 6: colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 5.0% + xylitol 3.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 7A (immediately) and Figure 7a (after 20 minutes).

[0092] The third round of in vivo sample 7: colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 5.0% + xylitol 4.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 7B (immediately) and Figure 7B (after 20 minutes).

[0093] The third round of in vivo sample 8: colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 5.0% + xylitol 5.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 7C (immediately) and Figure 7C (after 20 minutes).

[0094] The third round of in vivo sample 9: colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 1.0% + fructose 2.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 7D (immediately) and Figure 7D (after 20 minutes).

[0095] The third round of in vivo sample 10: colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 1.0% + fructose 3.0% + pectin 0.1%. The in vivo ultrasound images are shown in Figure 7E (immediate view) and Figure 7e (viewed when the stomach is half empty of the contrast agent).

[0096] The third round of in vivo sample 11: colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 1.0% + fructose 4.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 8A (immediately) and Figure 8a (after 20 minutes).

[0097] The third round of in vivo sample 12: colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 1.0% + fructose 5.0% + pectin 0.1%. The in vivo ultrasound images are shown in Figure 8B (immediately) and Figure 8B (after 20 minutes).

[0098] The third round of in vivo sample 13: colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 5.0% + fructose 2.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 8C (immediately) and Figure 8C (after 20 minutes).

[0099] The third round of in vivo sample 14: colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 5.0% + fructose 3.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 8D (immediately) and Figure 8D (after 20 minutes).

[0100] The third round of in vivo sample 15: colloidal microcrystalline cellulose RC591 0.5% + polyethylene glycol 6000 5.0% + fructose 4.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 8E (immediately) and Figure 8e (after 20 minutes).

[0101] In the third round of in vivo screening, all samples achieved an immediate image quality score of 10, but a small amount of light clustering still occurred, slightly impacting ultrasound imaging, and the gastric half-emptying time of the contrast agent was approximately 20 minutes. This third round of in vivo screening demonstrated that the combination of polyethylene glycol, xylitol, and fructose still produced a small amount of light clustering, which had a slight impact on ultrasound imaging, but could not completely eliminate the light clustering phenomenon. Therefore, a fourth round of in vivo imaging screening was conducted (adding different grades of magnesium aluminum silicate).

[0102] The fourth round of in vivo imaging screening of different types of magnesium aluminum silicate samples (formulation ratio is mass fraction): the imaging particulate matter is 8% microcrystalline cellulose PH102, 0.1% potassium sorbate, 0.05% citric acid, 0.03% sucralose, 0.5% cocoa powder, 0.2% simethicone emulsion (30%), and the composition of the compound suspending agent and the imaging results are as follows.

[0103] Fourth round in vivo sample 1: colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IC 0.4% + pectin 0.1%. In vivo ultrasound images are shown in Figure 9A (immediately) and Figure 9a (after 20 minutes).

[0104] Fourth round in vivo sample 2: colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IB 0.4% + pectin 0.1%. In vivo ultrasound images are shown in Figure 9B (immediately) and Figure 9B (after 20 minutes).

[0105] Fourth round in vivo sample 3: colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IC 0.4% + pectin 0.1%. In vivo ultrasound images are shown in Figure 9C (immediately) and Figure 9C (after 20 minutes).

[0106] Fourth round in vivo sample 4: colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IA 1.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 9D (immediately) and Figure 9d (after 20 minutes).

[0107] In the fourth round of in vivo screening, all samples achieved an immediate image quality score of 10 (with even better scores for roughness and air bubble effects), the gastric half-emptying time of the contrast agent was approximately 20 minutes, and no samples showed light clustering until the ultrasound contrast agent was completely emptied from the stomach. The results of this fourth round of in vivo screening demonstrated that magnesium aluminum silicate can effectively address the light clustering phenomenon. All samples showed no light clustering until the ultrasound contrast agent was completely emptied from the stomach, and the immediate images were more detailed, with clearer visualization of the gastric wall. To achieve optimal ultrasound imaging, we conducted a fifth round of in vivo screening to investigate the effectiveness of different types of magnesium aluminum silicate in combination with colloidal microcrystalline cellulose RC591 and polyethylene glycol in eliminating light clusters.

[0108] The fifth round of in vivo samples investigated the effect of different types of magnesium aluminum silicate compounded with colloidal microcrystalline cellulose RC591 and polyethylene glycol on eliminating photoclusters (the formula ratio is mass fraction): the imaging particulate matter was 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 composition of the compound suspending agent and the imaging results are as follows.

[0109] Fifth round in vivo sample 1: colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IA 0.4% + polyethylene glycol 4000 1.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 10A (immediate view) and Figure 10a (viewed when the stomach is half empty of the contrast agent).

[0110] Fifth round in vivo sample 2: colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IA 0.4% + polyethylene glycol 6000 1.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 10B (immediate view) and Figure 10b (viewed when the stomach is half empty of the contrast agent).

[0111] Fifth round in vivo sample 3: colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IA 0.4% + polyethylene glycol 8000 1.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 10C (immediate view) and Figure 10c (viewed when the stomach is half empty of the contrast agent).

[0112] Fifth round in vivo sample 4: colloidal microcrystalline cellulose RC591 1% + magnesium aluminum silicate IA 0.4% + polyethylene glycol 6000 2.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 10D (immediate view) and Figure 10d (viewed when the stomach is half empty of the contrast agent).

[0113] Fifth round in vivo sample 5: colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IA 0.4% + polyethylene glycol 6000 3.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 10E (immediate view) and Figure 10e (viewed when the stomach is half empty of the contrast agent).

[0114] Fifth round in vivo sample 6: colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IA 0.4% + polyethylene glycol 6000 4.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 11A (immediate view) and Figure 11a (viewed when the stomach is half empty of the contrast agent).

[0115] Fifth round in vivo sample 7: colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IA 0.4% + polyethylene glycol 6000 5.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 11B (immediate view) and Figure 11b (viewed when the stomach is half empty of the contrast agent).

[0116] Fifth round in vivo sample 8: colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IC 0.4% + polyethylene glycol 1500 1.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 11C (immediate view) and Figure 11c (viewed when the stomach is half empty of the contrast agent).

[0117] Fifth round in vivo sample 9: colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IC 0.4% + polyethylene glycol 4000 1.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 11D (immediate view) and Figure 11d (viewed when the stomach is half empty of the contrast agent).

[0118] Fifth round in vivo sample 10: colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IC 0.5% + polyethylene glycol 6000 1.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 11E (immediate view) and Figure 11e (viewed when the stomach is half empty of the contrast agent).

[0119] Fifth round in vivo sample 11: colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IC 0.5% + polyethylene glycol 8000 1.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 12A (immediate view) and Figure 12a (viewed when the stomach is half empty of the contrast agent).

[0120] Fifth round in vivo sample 12: colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IC 0.4% + polyethylene glycol 6000 2.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 12B (immediate view) and Figure 12B (viewed when the stomach is half empty of the contrast agent).

[0121] Fifth round in vivo sample 13: colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IC 0.4% + polyethylene glycol 6000 3.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 12C (immediate view) and Figure 12C (viewed when the stomach is half empty of the contrast agent).

[0122] Fifth round in vivo sample 14: colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IC 0.4% + polyethylene glycol 6000 4.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 12D (immediately) and Figure 12d (at the time of half-emptying of the stomach).

[0123] Fifth round in vivo sample 15: colloidal microcrystalline cellulose RC591 0.5% + magnesium aluminum silicate IC 0.4% + polyethylene glycol 6000 5.0% + pectin 0.1%. In vivo ultrasound images are shown in Figure 12E (immediate view) and Figure 12e (viewed when the stomach is half empty of the contrast agent).

[0124] In the fifth round of in vivo screening, all samples achieved an immediate image quality score of 10 (with virtually no deductions due to roughness or bubbles). The gastric half-emptying time of the contrast agent was approximately 20 minutes, and no light clustering was observed in any sample until the ultrasound contrast agent was completely emptied from the stomach. The results of this fifth round of screening demonstrated that polyethylene glycol (PEG) acts as a defoamer, improving immediate images. Its combination with magnesium aluminum silicate (IC) or IA effectively mitigates light clustering. The type and concentration of PEG were minimally affected, consistent with previous results.

[0125] Example 3.

[0126] 1. Recipe.

[0127] Microcrystalline cellulose PH102 (D 50 The mass fraction of the liquid powder is 4.0% (m / s), 0.75% (m / s), 0.75% (m / s), 0.02% (m / s), 1.0% (m / s), 0.1% (m / s), 0.02% (m / s), 0.5% (m / s), 0.1% (m / s), 0.2% (m / s), and 92.56% (m / s).

[0128] 2. Preparation method:

[0129] 1) Weigh the formulated amount of magnesium aluminum silicate, add an appropriate amount of water (25% of the total water amount), and hydrate at 80°C, 200 rpm, and stir for 1.5 hours. Then, high-shear homogenize the mixture at 10,000 rpm in a FLUKA-FA28 high-shear homogenizer for 3 minutes. Cool to room temperature and set aside.

[0130] 2) Weigh the formulated amount of microcrystalline cellulose, add an appropriate amount of water (25% of the total water volume), and stir at 200 rpm to mix thoroughly;

[0131] 3) Weigh the prescribed amount of PEG6000, add an appropriate amount of water (10% of the total water volume), and spin at 200 rpm until completely dissolved;

[0132] 4) Weigh the prescribed amount of colloidal microcrystalline cellulose and pectin, add an appropriate amount of water (25% of the total water), stir to disperse evenly, let it stand for 20 minutes (to allow the powder to be fully soaked), and then perform high shear homogenization at 10,000 rpm for 4 minutes;

[0133] 5) Weigh the formulated amount of cocoa powder, potassium sorbate, and sucralose, add an appropriate amount of water to dissolve (5% of the total water content), and degas for 30 minutes;

[0134] 6) Add the materials in 2, 3, and 4 to the magnesium aluminum silicate suspension at once, perform high shear homogenization at a homogenization speed of 10,000 rpm for 3 minutes, add the material in 5, and stir evenly; finally, add the formula amount of flavor, simethicone emulsion, and the remaining amount of water, and stir evenly;

[0135] 7) Degassing and filling.

[0136] We compared the ultrasound in vivo and in vitro imaging effects of Example 3 with those of Example 1 in the prior art (CN108939097B). The formulation and preparation method of Example 1 in the prior art were used to prepare an oral gastric ultrasound contrast agent as a comparative example, mainly to compare the effect of eliminating the light clusters in in vivo imaging. The experimental results are shown in Figure 13. Figure 13A shows a comparison of in vitro imaging. The left side is Example 3, and the right side is Example 1 in the prior art (CN108939097B). Violent shaking caused a large number of bubbles and the developer was immediately poured out for in vitro ultrasound imaging. At the moment of pouring out, both images showed a large amount of bubble interference, but the ultrasound image of Example 3 had recovered to complete uniformity within 1 minute, while the image of Example 1 in the prior art (CN108939097B) recovered to complete uniformity only after 5 minutes of violent shaking. After 5 minutes, the ultrasound on the same screen showed that the internal echoes of the in vitro imaging of both were uniform and consistent (see Figure 13A). Example B (Example 3) shows an ultrasound image superior to Example B (Example 1 in the prior art CN108939097B), with more uniform internal echoes, fewer mural bubbles, and a clearer display of the stomach wall. Over time, Example C (Example 3) shows that the ultrasound image remains uniform until the gastric half-emptying time, with no visible light clusters. However, Example C (Example 1 in the prior art CN108939097B) shows that the ultrasound image deteriorates, even exhibiting numerous light clusters, which severely impacts the display of the stomach wall.

[0137] We compared the ultrasound in vivo and in vitro imaging effects of Example 3 with a commercially available product (Beijing Zhongdao Aode Medical Technology Co., Ltd., Dongbeide brand, oral gastric ultrasound contrast agent), and showed that the imaging effect of Example 3 was slightly better than that of the commercially available product, see Figure 14. At the same time, we used the gastric ultrasound five-step nine-plane method (scanning standard formulated by inventor Liu Zhijun Liu Z, Guo J, Li Y, Zhang J, Zhang Y, Liu Z. Standardized Gastric Ultrasound Scanning Planes with Normal Anatomical Variability. Ultraschall Med. 2020 Jun; 41(3): 318-322.) to completely scan the gastric fundus, gastric body, gastric angle, gastric antrum long axis, short axis and coronal plane, indicating that after oral administration of the formula product of Example 3, gastric ultrasound can clearly scan various parts of the stomach, see Figure 15.

[0138] Example 4.

[0139] 1. Recipe.

[0140] Microcrystalline cellulose PH102 (D 50 The mass fraction of the liquid crystal display device is as follows: 1.0% (100 μm) with a mass fraction of 8.0%, 0.75% (colloidal microcrystalline cellulose Avicel RC-591), 0.25% (magnesium aluminum silicate IC), 0.05% (pectin), 1.0% (polyethylene glycol 6000), 0.1% (potassium sorbate), 0.05% (citric acid), 0.03% (sucralose), 0.6% (cocoa powder), 0.1% (milk flavor), 0.2% (simethicone emulsion (30%)), and 88.87% (deionized water).

[0141] 2. Preparation method: the same as the preparation method described in 2 of Example 3.

[0142] After oral administration of this embodiment, the immediate gastric ultrasound imaging effect and the gastric ultrasound imaging effect of the gastric half-emptying time are shown in FIG16A and FIG16a.

[0143] Example 5.

[0144] 1. Recipe.

[0145] Microcrystalline cellulose PH102 (D 50 The mass fraction of the liquid crystal display device is as follows: 10.0% (m / s), 0.4% (m / s), 0.4% (m / s), 0.05% (m / s), 0.1% (m / s), 0.05% (m / s), 0.1% (m / s), 0.03% (m / s), 0.1% (m / s), 0.2% (m / s), 0.0% (m / s), 0.5% (m / s), 0.2% (m / s), 100μm (m / s), 100μm (m / s), 0.4% (m / s), 0.4% (m / s), 0.05% (m / s), 0.05% (m / s), 0.1 ...

[0146] 2. Preparation method: the same as the preparation method described in 2 of Example 3.

[0147] After oral administration of this embodiment, the immediate gastric ultrasound imaging effect and the gastric ultrasound imaging effect of the gastric half-emptying time are shown in FIG16B and FIG16B .

[0148] Example 6.

[0149] 1. Recipe.

[0150] Silicified microcrystalline cellulose (D 50The mass fraction of the liquid crystal display device is 8.0%, the mass fraction of colloidal microcrystalline cellulose Avicel CL-611 is 0.5%, the mass fraction of magnesium aluminum silicate IA is 0.3%, the mass fraction of pectin is 0.05%, the mass fraction of polyethylene glycol 6000 is 1.0%, the mass fraction of sodium benzoate is 0.1%, the mass fraction of citric acid is 0.05%, the mass fraction of sucralose is 0.03%, the mass fraction of cocoa powder is 0.6%, the mass fraction of chocolate flavor is 0.1%, the mass fraction of simethicone emulsion (30%) is 0.2%, and the mass fraction of deionized water is 89.07%.

[0151] 2. Preparation method: the same as the preparation method described in 2 of Example 3.

[0152] After oral administration of this embodiment, the immediate gastric ultrasound imaging effect and the gastric ultrasound imaging effect of the gastric half-emptying time are shown in FIG16C and FIG16C.

[0153] Example 7.

[0154] 1. Recipe.

[0155] Microcrystalline cellulose (D 50 The mass fraction of the liquid crystal display device is 9.0%, the mass fraction of colloidal microcrystalline cellulose Avicel CL-591 is 0.8%, the mass fraction of magnesium aluminum silicate IA is 0.2%, the mass fraction of pectin is 0.1%, the mass fraction of polyethylene glycol 4000 is 1.0%, the mass fraction of sodium benzoate is 0.1%, the mass fraction of citric acid is 0.05%, the mass fraction of sucralose is 0.03%, the mass fraction of matcha powder is 0.6%, the mass fraction of matcha flavor is 0.1%, the mass fraction of simethicone emulsion (30%) is 0.2%, and the mass fraction of deionized water is 87.82%.

[0156] 2. Preparation method: the same as the preparation method described in 2 of Example 3.

[0157] After oral administration of this embodiment, the immediate gastric ultrasound imaging effect and the gastric ultrasound imaging effect of the gastric half-emptying time are shown in FIG16D and FIG16D.

[0158] Example 8.

[0159] 1. Recipe.

[0160] Microcrystalline cellulose PH102 (D 50The mass fraction of the liquid crystal display device is 8.0%, the mass fraction of colloidal microcrystalline cellulose Avicel RC-591 is 0.3%, the mass fraction of magnesium aluminum silicate IC is 0.2%, the mass fraction of pectin is 0.1%, the mass fraction of polyethylene glycol 6000 is 1.0%, the mass fraction of potassium sorbate is 0.1%, the mass fraction of citric acid is 0.05%, the mass fraction of sucralose is 0.03%, the mass fraction of cocoa powder is 0.5%, the mass fraction of chocolate flavor is 0.1%, the mass fraction of simethicone emulsion is 0.1%, and the mass fraction of deionized water is 89.52%.

[0161] 2. Preparation method: the same as the preparation method described in 2 of Example 3.

[0162] After oral administration of this embodiment, the immediate gastric ultrasound imaging effect and the gastric ultrasound imaging effect of the gastric half-emptying time are shown in FIG17A and FIG17a.

[0163] Example 9.

[0164] 1. Recipe.

[0165] Microcrystalline cellulose PH102 (D 50 : 100 μm) mass fraction is 10.0%, the mass fraction of colloidal microcrystalline cellulose Avicel RC-591 is 0.4%, the mass fraction of magnesium aluminum silicate IB is 0.2%, the mass fraction of pectin is 0.1%, the mass fraction of polyethylene glycol 4000 is 1.0%, the mass fraction of potassium sorbate is 0.1%, the mass fraction of citric acid is 0.05%, the mass fraction of saccharin sodium is 0.03%, the mass fraction of orange flavor is 0.1%, the mass fraction of simethicone emulsion is 0.2%, and the mass fraction of deionized water is 87.82%.

[0166] 2. Preparation method: the same as the preparation method described in 2 of Example 3.

[0167] After oral administration of this embodiment, the immediate gastric ultrasound imaging effect and the gastric ultrasound imaging effect of the gastric half-emptying time are shown in FIG17B and FIG17B .

[0168] Example 10.

[0169] 1. Recipe.

[0170] Microcrystalline cellulose PH102 (D 50 The mass fraction of the liquid crystal display device is 4.0% (100 μm), the mass fraction of colloidal microcrystalline cellulose Avicel RC591 is 0.75%, the mass fraction of magnesium aluminum silicate IC is 0.75%, the mass fraction of pectin is 0.02%, the mass fraction of polyethylene glycol 6000 is 1.0%, the mass fraction of potassium sorbate is 0.1%, the mass fraction of sucralose is 0.02%, the mass fraction of cocoa powder is 0.5%, the mass fraction of milk flavor is 0.1%, and the mass fraction of deionized water is 92.76%.

[0171] 2. Preparation method: the same as the preparation method described in 2 of Example 3.

[0172] After oral administration of this embodiment, the immediate gastric ultrasound imaging effect and the gastric ultrasound imaging effect of the gastric half-emptying time are shown in FIG17C and FIG17C.

[0173] Example 11.

[0174] 1. Recipe.

[0175] Microcrystalline cellulose PH102 (D 50 The mass fraction of the liquid crystal display device is 7.0%, the mass fraction of colloidal microcrystalline cellulose Avicel RC-591 is 0.5%, the mass fraction of magnesium aluminum silicate IC is 0.25%, the mass fraction of pectin is 0.1%, the mass fraction of polyethylene glycol 6000 is 1.0%, the mass fraction of potassium sorbate is 0.1%, the mass fraction of citric acid is 0.05%, the mass fraction of sucralose is 0.03%, the mass fraction of cocoa powder is 0.6%, the mass fraction of milk flavor is 0.1%, and the mass fraction of deionized water is 90.27%.

[0176] 2. Preparation method: the same as the preparation method described in 2 of Example 3.

[0177] After oral administration of this embodiment, the immediate gastric ultrasound imaging effect and the gastric ultrasound imaging effect of the gastric half-emptying time are shown in FIG17D and FIG17D.

[0178] Example 12.

[0179] 1. Recipe.

[0180] Microcrystalline cellulose PH102 (D 50 The mass fraction of the liquid crystal display device is 9.0%, the mass fraction of colloidal microcrystalline cellulose Avicel RC-591 is 0.4%, the mass fraction of magnesium aluminum silicate IC is 0.35%, the mass fraction of pectin is 0.1%, the mass fraction of polyethylene glycol 4000 is 1.0%, the mass fraction of potassium sorbate is 0.1%, the mass fraction of citric acid is 0.05%, the mass fraction of sucralose is 0.03%, the mass fraction of cocoa powder is 0.4%, and the mass fraction of deionized water is 88.57%.

[0181] 2. Preparation method: the same as the preparation method described in 2 of Example 3.

[0182] After oral administration of this embodiment, the immediate gastric ultrasound imaging effect and the gastric ultrasound imaging effect of the gastric half-emptying time are shown in FIG18A and FIG18a.

[0183] Example 13.

[0184] 1. Recipe.

[0185] Silicified microcrystalline cellulose (D 50 The mass fraction of the liquid crystal display device is 9.0%, the mass fraction of colloidal microcrystalline cellulose Avicel CL-611 is 0.4%, the mass fraction of magnesium aluminum silicate IB is 0.3%, the mass fraction of pectin is 0.05%, the mass fraction of polyethylene glycol 6000 is 1.0%, the mass fraction of sodium benzoate is 0.1%, the mass fraction of citric acid is 0.05%, the mass fraction of sucralose is 0.03%, the mass fraction of cocoa powder is 0.6%, the mass fraction of simethicone emulsion is 0.2%, the mass fraction of chocolate flavor is 0.1%, and the mass fraction of deionized water is 89.27%.

[0186] 2. Preparation method: the same as the preparation method described in 2 of Example 3.

[0187] After oral administration of this embodiment, the immediate gastric ultrasound imaging effect and the gastric ultrasound imaging effect of the gastric half-emptying time are shown in FIG18B and FIG18B .

[0188] Example 14.

[0189] 1. Recipe.

[0190] Microcrystalline cellulose (D 50 The mass fraction of the liquid crystal display device is 10.0%, the mass fraction of colloidal microcrystalline cellulose Avicel CL-611 is 0.3%, the mass fraction of magnesium aluminum silicate IA is 0.4%, the mass fraction of pectin is 0.1%, the mass fraction of polyethylene glycol 6000 is 1.0%, the mass fraction of potassium sorbate is 0.1%, the mass fraction of citric acid is 0.05%, the mass fraction of sucralose is 0.03%, the mass fraction of matcha powder is 0.6%, the mass fraction of matcha flavor is 0.1%, and the mass fraction of deionized water is 87.32%.

[0191] 2. Preparation method: the same as the preparation method described in 2 of Example 3.

[0192] After oral administration of this embodiment, the immediate gastric ultrasound imaging effect and the gastric ultrasound imaging effect of the gastric half-emptying time are shown in FIG18C and FIG18C.

[0193] Example 15.

[0194] 1. Recipe.

[0195] Microcrystalline cellulose PH102 (D 50The mass fraction of the liquid crystal display device is 8.0%, the mass fraction of colloidal microcrystalline cellulose Avicel CL-611 is 0.35%, the mass fraction of magnesium aluminum silicate IC is 0.25%, the mass fraction of pectin is 0.1%, the mass fraction of polyethylene glycol 6000 is 1.0%, the mass fraction of potassium sorbate is 0.1%, the mass fraction of citric acid is 0.05%, the mass fraction of sucralose is 0.03%, the mass fraction of cocoa powder is 0.5%, and the mass fraction of deionized water is 89.52%.

[0196] 2. Preparation method: the same as the preparation method described in 2 of Example 3.

[0197] After oral administration of this embodiment, the immediate gastric ultrasound imaging effect and the gastric ultrasound imaging effect of the gastric half-emptying time are shown in FIG18D and FIG18D.

[0198] Example 16.

[0199] 1. Recipe.

[0200] Microcrystalline cellulose (D 50 : 70μm) mass fraction of 7.0%, colloidal microcrystalline cellulose Avicel CL-611 mass fraction of 0.3%, magnesium aluminum silicate IB mass fraction of 0.2%, pectin mass fraction of 0.1%, polyethylene glycol 4000 mass fraction of 1.0%, potassium sorbate mass fraction of 0.1%, citric acid mass fraction of 0.05%, saccharin sodium mass fraction of 0.03%, matcha powder mass fraction of 0.5%, and deionized water mass fraction of 90.72%.

[0201] 2. Preparation method: the same as the preparation method described in 2 of Example 3.

[0202] After oral administration of this embodiment, the immediate gastric ultrasound imaging effect and the gastric ultrasound imaging effect of the gastric half-emptying time are shown in FIG19A and FIG19a.

[0203] Example 17.

[0204] 1. Recipe.

[0205] Microcrystalline cellulose PH102 (D 50 The mass fraction of the liquid crystal display device is 8.0%, the mass fraction of colloidal microcrystalline cellulose Avicel RC-591 is 0.25%, the mass fraction of magnesium aluminum silicate IA is 0.35%, the mass fraction of pectin is 0.05%, the mass fraction of polyethylene glycol 6000 is 1.0%, the mass fraction of potassium sorbate is 0.1%, the mass fraction of citric acid is 0.05%, the mass fraction of sucralose is 0.02%, the mass fraction of matcha powder is 0.5%, and the mass fraction of deionized water is 89.68%.

[0206] 2. Preparation method: the same as the preparation method described in 2 of Example 3.

[0207] After oral administration of this embodiment, the immediate gastric ultrasound imaging effect and the gastric ultrasound imaging effect of the gastric half-emptying time are shown in FIG19B and FIG19B .

[0208] Example 18.

[0209] 1. Recipe.

[0210] Silicified microcrystalline cellulose (D 50 The mass fraction of the liquid crystal display device is 8.0%, the mass fraction of colloidal microcrystalline cellulose Avicel RC-591 is 0.35%, the mass fraction of magnesium aluminum silicate IC is 0.35%, the mass fraction of pectin is 0.05%, the mass fraction of polyethylene glycol 4000 is 1.0%, the mass fraction of potassium sorbate is 0.1%, the mass fraction of citric acid is 0.05%, the mass fraction of sucralose is 0.03%, the mass fraction of cocoa powder is 0.5%, and the mass fraction of deionized water is 89.57%.

[0211] 2. Preparation method: the same as the preparation method described in 2 of Example 3.

[0212] After oral administration of this embodiment, the immediate gastric ultrasound imaging effect and the gastric ultrasound imaging effect of the gastric half-emptying time are shown in FIG19C and FIG19C.

[0213] Example 19.

[0214] 1. Recipe.

[0215] Microcrystalline cellulose PH102 (D 50 The mass fraction of the liquid crystal display device is 8.0%, the mass fraction of colloidal microcrystalline cellulose Avicel RC-591 is 0.35%, the mass fraction of magnesium aluminum silicate IA is 0.15%, the mass fraction of pectin is 0.15%, the mass fraction of polyethylene glycol 6000 is 1.0%, the mass fraction of potassium sorbate is 0.1%, the mass fraction of citric acid is 0.05%, the mass fraction of sucralose is 0.02%, the mass fraction of cocoa powder is 0.5%, the mass fraction of chocolate flavor is 0.1%, and the mass fraction of deionized water is 89.58%.

[0216] 2. Preparation method: the same as the preparation method described in 2 of Example 3.

[0217] After oral administration of this embodiment, the immediate gastric ultrasound imaging effect and the gastric ultrasound imaging effect of the gastric half-emptying time are shown in FIG19D and FIG19D.

[0218] The specific clinical application method of the technical solution of the present invention is described as follows:

[0219] The prepared ready-to-use oral gastric ultrasound contrast agent (300 mL) is packaged in a 650 mL bottle. Before use, open the bottle cap, add 300 mL of drinking water (drinking water of different temperatures can be added according to the subject's personal preference), and the final volume is brought to the 600 mL mark. Shake the bottle up and down for about 5 to 10 seconds to mix evenly. The subject can drink it directly orally. Oral administration of about 500 mL of the developer (the amount can be increased or decreased as appropriate according to the subject's stomach volume) can fill the stomach cavity and eliminate the interference of gastric gas, so that the gastric wall structure can be clearly displayed to meet the clinical requirements of gastric ultrasound examination.

[0220] The main ingredients in the formulation of the present invention are a combination of magnesium aluminum silicate, colloidal microcrystalline cellulose, and pectin, as well as microcrystalline cellulose or silicified microcrystalline cellulose. The combination of magnesium aluminum silicate, colloidal microcrystalline cellulose, and pectin allows the present invention to maintain excellent thixotropy and stability, continuing the product's ready-to-use characteristics and providing significant convenience in clinical use. More importantly, the combination of magnesium aluminum silicate and colloidal microcrystalline cellulose eliminates the photoclusters that are common in in vivo imaging with prior art products (CN108939097B). Polyethylene glycol, acting as a defoaming agent, improves immediate image quality, thereby ensuring excellent ultrasound imaging quality with the developer, providing a guarantee for clinical application.

Claims

1. A ready-to-use liquid oral gastric ultrasound contrast agent, characterized in that: Magnesium aluminum silicate is added into the developer formula as a composite suspending thickener.

2. The ultrasonic contrast agent according to claim 1, characterized in that: The compound suspending thickener also includes colloidal cellulose and pectin.

3. The ultrasonic contrast agent according to any one of claims 1 or 2, characterized in that: The developer is used in preparing a stomach ultrasound developer.

4. A ready-to-use liquid oral gastric ultrasound contrast agent, characterized in that: The developer is composed of a composite suspending thickener, ultrasonic imaging granular material, a defoaming agent, a flavoring agent, a preservative and water.

5. The ultrasonic contrast agent according to claim 4, characterized in that: The composite suspending thickener consists of magnesium aluminum silicate, colloidal cellulose and pectin.

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

7. The ultrasonic contrast agent according to claim 4, characterized in that: The developer is used in preparing a stomach ultrasound developer.

8. A method for preparing the ready-to-use liquid oral gastric ultrasound contrast agent according to any one of claims 4 to 6, characterized in that: The specific steps include: (1) Weigh the amount of magnesium aluminum silicate in the formula, add an appropriate amount of water, stir and hydrate at 80° C., and then homogenize; cool to room temperature for later use; (2) Weigh the formulated amount of microcrystalline cellulose, add an appropriate amount of water, stir to mix, and degas; (3) Weigh the prescribed amount of polyethylene glycol and add an appropriate amount of water until it is completely dissolved; (4) Weigh the prescribed amount of colloidal microcrystalline cellulose and pectin, add an appropriate amount of water, stir to disperse evenly, and let stand to homogenize; (5) Weigh the formula amount of flavoring agents, preservatives and other additives, add appropriate amount of water to disperse and dissolve, and degas; (6) Add the materials in steps (2), (3) and (4) to the aluminum magnesium silicate suspension obtained in step (1) in sequence, add the materials in step (5) after homogenization, and stir evenly; then add the formulated amount of flavor, the remaining amount of water, etc., and stir evenly; (7) Degassing and filling.

9. Use of the developer prepared by the preparation method according to claim 8 in preparing a gastric ultrasound developer.

Images