A gastrointestinal contrast agent and its preparation method

Abstract

The present invention provides a gastrointestinal contrast agent and a preparation method thereof, comprising the following raw materials in parts by weight: 60 - 80 parts of purified water, 10 - 20 parts of chitosan, 10 - 15 parts of β-glycerophosphate, 5 - 10 parts of microencapsulated ultrasonic reflection particles, 1 - 3 parts of sodium hyaluronate, 0.3 - 0.5 parts of edible pigment, and 0.1 - 0.3 parts of antioxidant. Chitosan and β-glycerophosphate can rapidly undergo a gelation reaction at physiological temperature to form a hydrogel structure. The formed hydrogel structure is not easily diluted or washed away by gastric juice or intestinal juice, ensuring the persistent presence of the contrast agent in the gastrointestinal tract, thereby increasing the filling rate and residence time in the gastrointestinal tract. Therefore, the contrast agent can contact the gastrointestinal mucosa more fully, thus more clearly showing the fine structure and pathological conditions of the gastrointestinal tract, helping to more comprehensively evaluate the health status of the gastrointestinal tract and reducing the possibility of missed diagnosis and misdiagnosis. By adding microencapsulated ultrasonic reflection particles, the contrast and clarity of the ultrasonic image are higher, and the structures in the image are more clearly visible.

Description

Technical Field

[0001] The present invention relates to the technical field of medical detection reagents, and specifically relates to a preparation method of a gastrointestinal contrast agent. Background Art

[0002] Gastrointestinal diseases are a wide range of diseases involving the digestive system, involving lesions of digestive organs such as the stomach, small intestine, and large intestine, including malignant diseases such as gastric cancer, colon cancer, rectal cancer, and gastrointestinal stromal tumors. These diseases not only seriously affect the quality of life of patients, but also pose a major threat to their lives. Therefore, early diagnosis of gastrointestinal malignant diseases is of extremely important significance. Through early screening and diagnosis, diseases can be detected and treated in a timely manner when they are still in the initial stage and have not undergone extensive metastasis, thereby significantly improving the cure rate, prolonging the survival period of patients, and effectively reducing the pain and economic burden of patients. In recent years, with the continuous development of science and technology, medical imaging has become an important auxiliary means for doctors in the process of diagnosing and treating diseases. Among them, contrast-enhanced ultrasound technology has been widely used in medical diagnosis, treatment, and post-treatment monitoring due to its advantages of being non-invasive, painless, and non-radiating. The use of contrast agents greatly improves the sensitivity and specificity of ultrasound diagnosis, so it plays a crucial role in contrast-enhanced ultrasound technology. Currently, common oral gastrointestinal contrast agents have a short residence time in the gastrointestinal tract, which may lead to difficulty in accurately capturing some subtle lesions. Summary of the Invention

[0003] In view of this, the present invention proposes a preparation method of a gastrointestinal contrast agent to solve the above problems.

[0004] The technical solution of the present invention is realized as follows: A gastrointestinal contrast agent includes the following raw materials in parts by weight: 60 - 80 parts of purified water, 10 - 20 parts of chitosan, 10 - 15 parts of β-glycerophosphate, 5 - 10 parts of microencapsulated ultrasound reflection particles, 1 - 3 parts of sodium hyaluronate, 0.3 - 0.5 parts of edible pigment, and 0.1 - 0.3 parts of antioxidant.

[0005] Further, a gastrointestinal contrast agent includes the following raw materials in parts by weight: 70 parts of purified water, 15 parts of chitosan, 12.5 parts of β-glycerophosphate, 7.5 parts of microencapsulated ultrasound reflection particles, 2 parts of sodium hyaluronate, 0.4 parts of edible pigment, and 0.2 parts of antioxidant.

[0006] Further, the edible pigment is one of chlorophyll, curcumin, betanin, carmine, saffron pigment, purple cabbage pigment, and butterfly pea flower pigment.

[0007] Further, the antioxidant is composed of vitamin C, dibutylhydroxytoluene, and tea polyphenols in a mass ratio of (3 - 5):(2 - 4):(1 - 3).

[0008] Further, the microencapsulated ultrasonic reflection particles are prepared by the following method: adding polyhydroxyalkanoate into chloroform, and carrying out ultrasonic stirring for 20 - 30 min under the conditions of ultrasonic power of 100 - 300 W and ultrasonic frequency of 40 - 60 kHz to obtain a polymer solution; stirring nano - zinc oxide with a particle size of 50 - 100 nm at 500 - 1000 r / min for 10 - 20 min to disperse it in phosphate buffer solution to form an inner aqueous phase; adding span 80 to the inner aqueous phase and slowly dropping the above - mentioned polymer solution, and carrying out ultrasonic treatment for 10 - 20 min under the conditions of ultrasonic power of 100 - 200 W and ultrasonic frequency of 20 - 40 kHz to form a water - in - oil emulsion; adding the water - in - oil emulsion to a polyvinyl alcohol solution with a concentration of 4 - 6 wt%, and stirring at 300 - 500 r / min for 20 - 30 min to obtain a water - in - oil - in - water multiple emulsion; placing the water - in - oil - in - water multiple emulsion at 30 - 40 °C and stirring at 200 - 400 r / min for 40 - 60 min to make the polyhydroxyalkanoate solidify into a film on the surface of the emulsion droplets to form microcapsules; washing the microcapsules 2 - 3 times with deionized water and ethanol; drying the washed microcapsules at a vacuum degree of 30 - 50 kPa and 40 - 60 °C for 4 - 6 h to obtain the microencapsulated ultrasonic reflection particles.

[0009] Further, the mass - to - volume ratio of polyhydroxyalkanoate to chloroform is (1.0 - 1.5):(5.0 - 10.0) g / mL; the mass - to - volume ratio of the nano - zinc oxide to the phosphate buffer solution is (0.1 - 0.2):(4.0 - 10.0) g / mL; the volume ratio of the inner aqueous phase, span 80, and the polymer solution is (1.0 - 1.5):(0.2 - 0.4):(3.0 - 5.0); the volume ratio of the water - in - oil emulsion to the polyvinyl alcohol solution is (1 - 2):(6 - 10).

[0010] Further, a preparation method of a gastrointestinal contrast agent includes the following steps:

[0011] S1. Weigh the pure water, chitosan, β - glycerophosphate, microencapsulated ultrasonic reflection particles, sodium hyaluronate, edible pigment, and antioxidant in parts by weight, and set aside;

[0012] S2. Take one - third of the parts by weight of pure water, add chitosan to it, and stir to dissolve to obtain a chitosan solution;

[0013] S3. Add β - glycerophosphate to the above - mentioned chitosan solution, and stir to dissolve to obtain a composite solution I;

[0014] S4. Add the remaining pure water to the composite solution 1, and add sodium hyaluronate, edible pigment, and antioxidant, and stir to dissolve to obtain a composite solution II;

[0015] S5. Add the microencapsulated ultrasonic reflection particles into the composite solution II, stir evenly, and place them in a homogenizer for homogenization treatment to obtain a gastrointestinal contrast agent.

[0016] Further, the stirring speed in S2 is 200 - 500 r / min and the stirring time is 20 - 30 min, the stirring speed in S3 is 200 - 500 r / min and the stirring time is 5 - 15 min, the stirring speed in S4 is 200 - 500 r / min and the stirring time is 10 - 20 min, and the stirring speed in S5 is 100 - 300 r / min and the stirring time is 5 - 10 min.

[0017] Further, the homogenization treatment in S5 is carried out at a homogenization pressure of 20 - 40 MPa for 5 - 15 min.

[0018] Compared with the prior art, the beneficial effects of the present invention are as follows: At physiological temperature, hydrogen bonds are formed between the amino groups on the chitosan molecular chain and the phosphate ions in the β - glycerophosphate molecule, enhancing the interaction between the chitosan molecular chain and β - glycerophosphate, resulting in a rapid solution - to - gel transition of the solution. At the same time, the hydrophobic interaction between chitosan molecular chains is also enhanced. These interactions together promote the formation of a stable three - dimensional network structure, that is, a hydrogel structure is formed. The formed hydrogel structure has good stability and is not easily diluted or washed away by gastric juice and intestinal juice, ensuring the persistent presence of the contrast agent in the gastrointestinal tract, thereby improving the filling rate and significantly prolonging its residence time in the gastrointestinal tract. And the viscoelasticity of the hydrogel enables the contrast agent to maintain a certain shape and volume in the gastrointestinal tract and is not easily emptied quickly, which helps the contrast agent to maintain a high filling rate in the gastrointestinal tract for a long time. At the same time, sodium hyaluronate can further improve the viscoelasticity of the hydrogel, making the contrast agent more viscous in the gastrointestinal tract, thereby increasing its filling rate and residence time in the gastrointestinal tract. Sodium hyaluronate also has good biocompatibility and biological activity, can interact with the gastrointestinal mucosa, and further delays the emptying speed of the contrast agent, thereby increasing the residence time of the contrast agent. Therefore, the contrast agent can contact the gastrointestinal mucosa more fully, thus more clearly showing the fine structure and pathological conditions of the gastrointestinal tract, helping to more comprehensively evaluate the health status of the gastrointestinal tract and reducing the possibility of missed diagnosis and misdiagnosis.

[0019] The present invention endows the contrast agent with distinct colors by adding food coloring, making it more prominent during the ultrasonic imaging process, facilitating doctors to accurately identify and locate the target area. The distinct color contrast helps doctors quickly distinguish normal tissues from diseased tissues, thereby improving the accuracy and efficiency of diagnosis.

[0020] In the present invention, by adding microencapsulated ultrasonic reflection particles, when ultrasonic waves encounter these particles, strong backscattering occurs, generating stronger ultrasonic signals, making the contrast and clarity of ultrasonic images higher. Therefore, the structures in the images are more clearly visible. By enhancing the contrast and clarity of the images, the microencapsulated ultrasonic reflection particles help doctors more accurately identify key information such as diseased tissues and vascular structures, thereby improving the accuracy and reliability of diagnosis. Detailed implementation manner

[0021] To better understand the technical content of the present invention, specific embodiments are provided below to further illustrate the present invention.

[0022] Unless otherwise specified, the experimental methods used in the embodiments of the present invention are all conventional methods.

[0023] Unless otherwise specified, the materials, reagents, etc. used in the embodiments of the present invention can all be obtained from commercial channels.

[0024] Embodiment 1

[0025] A gastrointestinal contrast agent comprises the following raw materials in parts by weight: 60 parts of purified water, 10 parts of chitosan, 10 parts of β-glycerophosphate, 5 parts of microencapsulated ultrasonic reflection particles, 1 part of sodium hyaluronate, 0.3 part of edible pigment, and 0.1 part of antioxidant. The edible pigment is chlorophyll, and the antioxidant is composed of vitamin C, dibutylhydroxytoluene, and tea polyphenols in a mass ratio of 3:2:1.

[0026] Among them, the microencapsulated ultrasonic reflection particles are prepared by the following method: adding polyhydroxyalkanoate into chloroform, and ultrasonically stirring for 30 min under the conditions of ultrasonic power of 100 W and ultrasonic frequency of 40 kHz to obtain a polymer solution. The mass-volume ratio of polyhydroxyalkanoate to chloroform is 1.0:5.0 g / mL. Stir nano-zinc oxide with a particle size of 50 nm at 500 r / min for 20 min to disperse it in phosphate buffer solution to form an inner aqueous phase. The mass-volume ratio of nano-zinc oxide to phosphate buffer solution is 0.1:4.0 g / mL. Add Span 80 to the inner aqueous phase and slowly drop the above polymer solution, and ultrasonically treat for 20 min under the conditions of ultrasonic power of 100 W and ultrasonic frequency of 20 kHz to form a water-in-oil emulsion. The volume ratio of the inner aqueous phase, Span 80, and the polymer solution is 1.0:0.2:3.0. Add the water-in-oil emulsion to a 4 wt% polyvinyl alcohol solution and stir at 300 r / min for 30 min to obtain a water-in-oil-in-water double emulsion. The volume ratio of the water-in-oil emulsion to the polyvinyl alcohol solution is 1:6. Place the water-in-oil-in-water double emulsion at 30 °C and stir at 200 r / min for 60 min to make the polyhydroxyalkanoate solidify into a film on the surface of the emulsion droplets to form microcapsules. Wash the microcapsules twice with deionized water and ethanol. Dry the washed microcapsules at a vacuum degree of 30 kPa and 40 °C for 6 h to obtain microencapsulated ultrasonic reflection particles.

[0027] The described gastrointestinal contrast agent is prepared by the following method, specifically including the following steps:

[0028] S1. Weigh the specified parts of purified water, chitosan, β-glycerophosphate, microencapsulated ultrasonic reflection particles, sodium hyaluronate, edible pigment, and antioxidant by weight, and set aside.

[0029] S2. Take one-third of the purified water, add chitosan to it, and stir at 200 r / min for 30 min to obtain a chitosan solution.

[0030] S3. Add β-glycerophosphate to the above chitosan solution and stir at 200 r / min for 15 min to obtain composite solution I.

[0031] S4. Add the remaining purified water to composite solution 1, and add sodium hyaluronate, edible pigment, and antioxidant, and stir at 200 r / min for 20 min to obtain composite solution II.

[0032] S5. Add the microencapsulated ultrasonic reflection particles to composite solution II, stir at 100 r / min for 10 min, and place it in a homogenizer to homogenize for 15 min under a homogenization pressure of 20 MPa to obtain a gastrointestinal contrast agent.

[0033] Example 2

[0034] A gastrointestinal contrast agent, comprising the following raw materials in parts by weight: 60 parts of purified water, 10 parts of chitosan, 10 parts of β-glycerophosphate, 5 parts of microencapsulated ultrasonic reflection particles, 1 part of sodium hyaluronate, 0.3 part of edible pigment, and 0.1 part of antioxidant. The edible pigment is curcumin, and the antioxidant is composed of vitamin C, dibutylhydroxytoluene, and tea polyphenol in a mass ratio of 3:2:1.

[0035] Among them, the microencapsulated ultrasonic reflection particles are prepared by the following method: adding polyhydroxyalkanoate to chloroform, and ultrasonically stirring for 20 min under the conditions of an ultrasonic power of 300 W and an ultrasonic frequency of 60 kHz to obtain a polymer solution. The mass-volume ratio of polyhydroxyalkanoate to chloroform is 1.0:5.0 g / mL. Stirring nano-zinc oxide with a particle size of 50 nm at 1000 r / min for 10 min to disperse it in phosphate buffer solution to form an inner aqueous phase. The mass-volume ratio of nano-zinc oxide to phosphate buffer solution is 0.1:4.0 g / mL. Adding span 80 to the inner aqueous phase and slowly dropping the above polymer solution, and ultrasonically treating for 10 min under the conditions of an ultrasonic power of 200 W and an ultrasonic frequency of 40 kHz to form a water-in-oil emulsion. The volume ratio of the inner aqueous phase, span 80, and the polymer solution is 1.0:0.2:3.0. Adding the water-in-oil emulsion to a 4 wt% polyvinyl alcohol solution and stirring at 500 r / min for 30 min to obtain a water-in-oil-in-water double emulsion. The volume ratio of the water-in-oil emulsion to the polyvinyl alcohol solution is 1:6. Placing the water-in-oil-in-water double emulsion at 40 °C and stirring at 400 r / min for 40 min to cause the polyhydroxyalkanoate to solidify into a film on the surface of the emulsion droplets to form microcapsules. Washing the microcapsules 3 times with deionized water and ethanol. Drying the washed microcapsules at a vacuum degree of 50 kPa and 60 °C for 4 h to obtain microencapsulated ultrasonic reflection particles.

[0036] The described gastrointestinal contrast agent is prepared by the following method, specifically including the following steps:

[0037] S1. Weigh the purified water, chitosan, β-glycerophosphate, microencapsulated ultrasonic reflection particles, sodium hyaluronate, edible pigment, and antioxidant in the described parts by weight and set aside.

[0038] S2. Take one-third of the parts by weight of purified water, add chitosan to it, and stir at 500 r / min for 20 min to obtain a chitosan solution.

[0039] S3. Add β-glycerophosphate to the above chitosan solution and stir at 500 r / min for 5 min to obtain composite solution I.

[0040] S4. Add the remaining purified water to the composite solution 1, and add sodium hyaluronate, edible pigment, and antioxidant. Stir at 500 r / min for 10 min to obtain composite solution II.

[0041] S5. Add the microencapsulated ultrasonic reflection particles to the composite solution II. Stir at 300 r / min for 5 min, and place it in a homogenizer to homogenize for 5 min under the condition of a homogenization pressure of 40 MPa to obtain a gastrointestinal contrast agent.

[0042] Example 3

[0043] A gastrointestinal contrast agent, comprising the following raw materials in parts by weight: 70 parts of purified water, 15 parts of chitosan, 12.5 parts of β-glycerophosphate, 7.5 parts of microencapsulated ultrasonic reflection particles, 2 parts of sodium hyaluronate, 0.4 part of edible pigment, 0.2 part of antioxidant. The edible pigment is carmine, and the antioxidant is composed of vitamin C, dibutylhydroxytoluene, and tea polyphenols with a mass ratio of 4:3:2.

[0044] Among them, the microencapsulated ultrasonic reflection particles are prepared by the following method: Add polyhydroxyalkanoate to chloroform, and ultrasonically stir at an ultrasonic power of 200 W and an ultrasonic frequency of 50 kHz for 25 min to obtain a polymer solution. The mass-volume ratio of polyhydroxyalkanoate to chloroform is 1.2:7.5 g / mL. Stir nano-zinc oxide with a particle size of 75 nm at 750 r / min for 15 min to disperse it in phosphate buffer solution to form an inner aqueous phase. The mass-volume ratio of nano-zinc oxide to phosphate buffer solution is 0.15:7.00 g / mL. Add span 80 to the inner aqueous phase and slowly drop the above polymer solution, and ultrasonically treat it at an ultrasonic power of 150 W and an ultrasonic frequency of 30 kHz for 15 min to form a water-in-oil emulsion. The volume ratio of the inner aqueous phase, span 80, and the polymer solution is 1.2:0.3:4.0. Add the water-in-oil emulsion to a 5 wt% polyvinyl alcohol solution and stir at 400 r / min for 25 min to obtain a water-in-oil-in-water multiple emulsion. The volume ratio of the water-in-oil emulsion to the polyvinyl alcohol solution is 1.5:8.0. Place the water-in-oil-in-water multiple emulsion at 35 °C and stir at 300 r / min for 50 min to make the polyhydroxyalkanoate solidify into a film on the surface of the emulsion droplets to form microcapsules. Wash the microcapsules 3 times with deionized water and ethanol. Dry the washed microcapsules at a vacuum degree of 40 kPa and 50 °C for 5 h to obtain microencapsulated ultrasonic reflection particles.

[0045] The described gastrointestinal contrast agent is prepared by the following method, specifically including the following steps:

[0046] S1. Weigh the above-mentioned parts of purified water, chitosan, β-glycerophosphate, microencapsulated ultrasonic reflection particles, sodium hyaluronate, edible pigment, and antioxidant by weight and set aside.

[0047] S2. Take one-third of the amount of pure water, add chitosan thereto, stir at 350 r / min for 25 min to obtain a chitosan solution.

[0048] S3. Add β-glycerophosphate to the above chitosan solution, stir at 350 r / min for 10 min to obtain Composite Solution I.

[0049] S4. Add the remaining pure water to Composite Solution 1, and add sodium hyaluronate, edible pigment, antioxidant, stir at 350 r / min for 15 min to obtain Composite Solution II.

[0050] S5. Add microencapsulated ultrasonic reflection particles to Composite Solution II, stir at 200 r / min for 7.5 min, and place it in a homogenizer to homogenize for 10 min under the condition of a homogenization pressure of 30 MPa to obtain a gastrointestinal contrast agent.

[0051] Example 4

[0052] A gastrointestinal contrast agent, comprising the following raw materials in parts by weight: 80 parts of pure water, 20 parts of chitosan, 15 parts of β-glycerophosphate, 10 parts of microencapsulated ultrasonic reflection particles, 3 parts of sodium hyaluronate, 0.5 part of edible pigment, 0.3 part of antioxidant. The edible pigment therein is saffron pigment, and the antioxidant is composed of vitamin C, dibutylhydroxytoluene, and tea polyphenol in a mass ratio of 5:4:3.

[0053] Among them, the microencapsulated ultrasonic reflection particles are prepared by the following method: adding polyhydroxyalkanoate into chloroform, and carrying out ultrasonic stirring for 30 min under the conditions of ultrasonic power of 100 W and ultrasonic frequency of 40 kHz to obtain a polymer solution. The mass-volume ratio of polyhydroxyalkanoate to chloroform is 1.5:10.0 g / mL. Stirring nano-zinc oxide with a particle size of 50 nm at 500 r / min for 20 min to disperse it in phosphate buffer solution to form an inner aqueous phase. The mass-volume ratio of nano-zinc oxide to phosphate buffer solution is 0.2:10.0 g / mL. Adding Span 80 to the inner aqueous phase and slowly dropping the above polymer solution, and carrying out ultrasonic treatment for 20 min under the conditions of ultrasonic power of 100 W and ultrasonic frequency of 20 kHz to form a water-in-oil emulsion. The volume ratio of the inner aqueous phase, Span 80, and the polymer solution is 1.5:0.4:5.0. Adding the water-in-oil emulsion to a 6 wt% polyvinyl alcohol solution and stirring at 300 r / min for 30 min to obtain a water-in-oil-in-water double emulsion. The volume ratio of the water-in-oil emulsion to the polyvinyl alcohol solution is 2:10. Placing the water-in-oil-in-water double emulsion at 30 °C and stirring at 200 r / min for 60 min to make the polyhydroxyalkanoate solidify into a film on the surface of the emulsion droplets to form microcapsules. Washing the microcapsules twice with deionized water and ethanol. Drying the washed microcapsules at a vacuum degree of 30 kPa and 40 °C for 6 h to obtain microencapsulated ultrasonic reflection particles.

[0054] The described gastrointestinal contrast agent is prepared by the following method, which specifically includes the following steps:

[0055] S1. Weigh the pure water, chitosan, β-glycerophosphate, microencapsulated ultrasonic reflection particles, sodium hyaluronate, edible pigment, and antioxidant in the described parts by weight and set aside.

[0056] S2. Take one-third of the parts by weight of pure water, add chitosan to it, and stir at 200 r / min for 30 min to obtain a chitosan solution.

[0057] S3. Add β-glycerophosphate to the above chitosan solution and stir at 200 r / min for 15 min to obtain Compound Solution I.

[0058] S4. Add the remaining pure water to Compound Solution 1, and add sodium hyaluronate, edible pigment, and antioxidant, and stir at 200 r / min for 20 min to obtain Compound Solution II.

[0059] S5. Add the microencapsulated ultrasonic reflection particles to Compound Solution II, stir at 100 r / min for 10 min, and place it in a homogenizer to carry out homogenization at a homogenization pressure of 20 MPa for 15 min to obtain a gastrointestinal contrast agent.

[0060] Example 5

[0061] A gastrointestinal contrast agent, comprising the following raw materials in parts by weight: 80 parts of purified water, 20 parts of chitosan, 15 parts of β-glycerophosphate, 10 parts of microencapsulated ultrasonic reflection particles, 3 parts of sodium hyaluronate, 0.5 part of edible pigment, and 0.3 part of antioxidant. The edible pigment is purple cabbage pigment, and the antioxidant is composed of vitamin C, dibutylhydroxytoluene, and tea polyphenol in a mass ratio of 5:4:3.

[0062] Among them, the microencapsulated ultrasonic reflection particles are prepared by the following method: Add polyhydroxyalkanoate to chloroform, and carry out ultrasonic stirring for 20 min under the conditions of ultrasonic power of 300 W and ultrasonic frequency of 60 kHz to obtain a polymer solution. The mass-volume ratio of polyhydroxyalkanoate to chloroform is 1.5:10.0 g / mL. Stir nano-zinc oxide with a particle size of 100 nm at 1000 r / min for 10 min to disperse it in phosphate buffer solution to form an inner aqueous phase. The mass-volume ratio of nano-zinc oxide to phosphate buffer solution is 0.2:10.0 g / mL. Add Span 80 to the inner aqueous phase and slowly drop the above polymer solution, and carry out ultrasonic treatment for 10 min under the conditions of ultrasonic power of 200 W and ultrasonic frequency of 40 kHz to form a water-in-oil emulsion. The volume ratio of the inner aqueous phase, Span 80, and the polymer solution is 1.5:0.4:5.0. Add the water-in-oil emulsion to a 6 wt% polyvinyl alcohol solution and stir at 500 r / min for 20 min to obtain a water-in-oil-in-water double emulsion. The volume ratio of the water-in-oil emulsion to the polyvinyl alcohol solution is 2:10. Place the water-in-oil-in-water double emulsion at 40 °C and stir at 400 r / min for 40 min to make the polyhydroxyalkanoate solidify into a film on the surface of the emulsion droplets to form microcapsules. Wash the microcapsules 3 times with deionized water and ethanol. Dry the washed microcapsules at a vacuum degree of 50 kPa and 60 °C for 4 h to obtain microencapsulated ultrasonic reflection particles.

[0063] The described gastrointestinal contrast agent is prepared by the following method, specifically including the following steps:

[0064] S1. Weigh the purified water, chitosan, β-glycerophosphate, microencapsulated ultrasonic reflection particles, sodium hyaluronate, edible pigment, and antioxidant in the described parts by weight and set aside.

[0065] S2. Take one-third of the parts by weight of purified water, add chitosan to it, and stir at 500 r / min for 20 min to obtain a chitosan solution.

[0066] S3. Add β-glycerophosphate to the above chitosan solution and stir at 500 r / min for 5 min to obtain Compound Solution I.

[0067] S4. Add the remaining purified water into the composite solution 1, and add sodium hyaluronate, edible pigment, and antioxidant, and stir at 500 r / min for 10 min to obtain composite solution II.

[0068] S5. Add the microencapsulated ultrasonic reflection particles into the composite solution II, stir at 300 r / min for 5 min, and place it in a homogenizer to homogenize for 5 min under the condition of a homogenization pressure of 40 MPa to obtain a gastrointestinal contrast agent.

[0069] Comparative Example 1

[0070] This comparative example is compared with Example 3. The difference is that the gastrointestinal contrast agent is purified water.

[0071] Comparative Example 2

[0072] This comparative example is compared with Example 3. The difference is that the gastrointestinal contrast agent raw material does not contain chitosan.

[0073] Comparative Example 3

[0074] This comparative example is compared with Example 3. The difference is that the gastrointestinal contrast agent raw material does not contain β-glycerophosphate.

[0075] Comparative Example 4

[0076] This comparative example is compared with Example 3. The difference is that the gastrointestinal contrast agent raw material does not contain microencapsulated ultrasonic reflection particles.

[0077] Comparative Example 5

[0078] This comparative example is compared with Example 3. The difference is that the gastrointestinal contrast agent raw material does not contain edible pigment.

[0079] Ultrasonic contrast examination

[0080] Select 90 patients with gastrointestinal diseases such as abdominal distension, abdominal pain, and decreased appetite. Among them, there are 43 males and 47 females, and the age range is between 40 and 70 years old, with an average age of 53.5 years. The patients fast and refrain from drinking water for 8 h before the examination and are examined in the morning. The patients take the supine position, and an ultrasonic diagnostic device is used for the examination, and the probe frequency is 3.0 MHz. The patients are divided into 9 groups, and each group of patients orally takes 300 ml of the contrast agents prepared in Examples 1-5 and Comparative Examples 1-4. The gastric cavity filling conditions are examined 1 h and 2 h later, and at the same time, the residence time of the contrast agent in the gastric cavity of the patients is recorded. The examination is carried out by the same doctor on the same machine. The average value of each group of examination results is recorded in Table 1.

[0081] Table 1

[0082]

[0083] As can be seen from Table 1, the contrast agents prepared in Examples 1-5 can effectively fill the gastrointestinal tract. They still have a high filling rate 1 hour and 2 hours after taking the contrast agent, and the contrast agent stays in the gastrointestinal tract for a long time. Therefore, the contrast agent can come into contact with the gastrointestinal mucosa more fully, thus showing the fine structure and pathological conditions of the gastrointestinal tract more clearly, helping to more comprehensively evaluate the health status of the gastrointestinal tract, and reducing the possibility of missed diagnosis and misdiagnosis. Among them, the effect of Example 3 is better.

[0084] By comparing Example 3 with Comparative Example 1, in Example 3, chitosan and β-glycerophosphate can rapidly undergo a gelation reaction at physiological temperature to form a hydrogel structure. The formed hydrogel structure has good stability and is not easily diluted or washed away by gastric juice, ensuring the persistent presence of the contrast agent in the gastrointestinal tract, thereby increasing the filling rate and significantly prolonging its residence time in the gastrointestinal tract. Moreover, the viscoelasticity of the hydrogel enables the contrast agent to maintain a certain shape and volume in the gastric cavity and is not easily emptied quickly, which helps the contrast agent to maintain a high filling rate in the gastrointestinal tract for a long time. At the same time, sodium hyaluronate can further improve the viscoelasticity of the hydrogel, making the contrast agent more viscous in the gastrointestinal tract, thereby increasing its filling rate and residence time in the gastrointestinal tract. Sodium hyaluronate also has good biocompatibility and biological activity, can interact with the gastrointestinal mucosa, and further delays the emptying rate of the contrast agent, thereby increasing the residence time of the contrast agent. Therefore, the contrast agent prepared in Example 3 has a filling rate of 90% at 1 hour, a filling rate of 86% at 2 hours, and a residence time of 4.8 hours.

[0085] By comparing Example 3 with Comparative Examples 2-3, in Example 3, the β-glycerophosphate molecule has thermosensitivity. At physiological temperature, hydrogen bonds are formed between the amino groups on the chitosan molecular chain and the phosphate ions in the β-glycerophosphate molecule, enhancing the interaction between the chitosan molecular chain and β-glycerophosphate, resulting in a rapid transition of the solution to a gel. At the same time, the hydrophobic interaction between the chitosan molecular chains is also enhanced. These interactions together promote the formation of a stable three-dimensional network structure, that is, a hydrogel structure. The interaction between chitosan and β-glycerophosphate is the basis for the formation of a stable hydrogel structure. The lack of any one of these raw materials will result in the inability to form an effective gel network structure, thus affecting the filling effect and residence time of the contrast agent.

[0086] By comparing Example 3 with Comparative Example 4, although the food coloring has no effect on the filling rate and residence time. However, by adding food coloring, the contrast agent is given a distinct color, making it more conspicuous during the ultrasound imaging process, facilitating accurate identification and positioning of the target area by doctors. The distinct color contrast helps doctors quickly distinguish normal tissues from diseased tissues, thereby improving the accuracy and efficiency of diagnosis.

[0087] By comparing Example 3 with Comparative Example 5, in Example 3, the polyhydroxyalkanoate in the microencapsulated ultrasonic reflection particles solidifies into a viscoelastic film on the surface of the emulsion droplets. When the microencapsulated ultrasonic reflection particles are dispersed in the contrast agent, it can increase the overall viscoelasticity of the contrast agent, thus contributing to the improvement of the filling rate and residence time. The microencapsulated ultrasonic reflection particles have the characteristic of strongly scattering ultrasonic waves. When ultrasonic waves encounter these particles, strong backscattering will occur, generating stronger ultrasonic signals, making the contrast and clarity of the ultrasonic image higher. Therefore, the structures in the image are more clearly visible. By enhancing the contrast and clarity of the image, the microencapsulated ultrasonic reflection particles help doctors more accurately identify key information such as diseased tissues and vascular structures, thereby improving the accuracy and reliability of diagnosis. In the diagnosis of diseases such as tumors, the microencapsulated ultrasonic reflection particles can significantly improve the clarity of the lesion boundary, helping doctors more accurately determine the scope and location of the lesion. The microencapsulated ultrasonic reflection particles have good stability and can maintain integrity and activity for a long time in the gastrointestinal tract, which helps to ensure the consistency and reliability of the contrast agent during the whole examination process. Since the microencapsulated ultrasonic reflection particles can significantly enhance the contrast and clarity of the ultrasonic image, doctors can obtain the required information faster, thus shortening the examination time and reducing the burden and discomfort of patients. The microencapsulated ultrasonic reflection particles in the present invention are made of materials with good biocompatibility, are non-toxic and harmless to the human body, and are easy to be excreted from the body.

[0088] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A gastrointestinal contrast agent, characterized in that: The invention comprises the following raw materials in parts by weight: 60-80 parts of purified water, 10-20 parts of chitosan, 10-15 parts of sodium β-glycerophosphate, 5-10 parts of microencapsulated ultrasound reflective particles, 1-3 parts of sodium hyaluronate, 0.3-0.5 parts of food coloring, and 0.1-0.3 parts of antioxidant; The microencapsulated ultrasonic reflective particles are prepared by the following method: adding polyhydroxyalkanoate to chloroform, and ultrasonically stirring for 20-30 minutes under the conditions of ultrasonic power of 100-300W and ultrasonic frequency of 40-60kHz to obtain a polymer solution; stirring nano zinc oxide with a particle size of 50-100nm at 500-1000r / min for 10-20min to disperse it in a phosphate buffer to form an inner water phase; adding Span 80 to the inner water phase and slowly dropping the polymer solution, and ultrasonically treating for 10-20 minutes under the conditions of ultrasonic power of 100-200W and ultrasonic frequency of 20-40kHz. min to form an oil-in-water emulsion; adding the oil-in-water emulsion to a polyvinyl alcohol solution with a concentration of 4-6wt%, stirring at 300-500r / min for 20-30min to obtain a water-in-oil-in-water double emulsion; placing the water-in-oil-in-water double emulsion at 30-40°C and stirring at 200-400r / min for 40-60min to allow the polyhydroxyalkanoate to solidify into a film on the surface of the emulsion droplets to form microcapsules; washing the microcapsules with deionized water and ethanol for 2-3 times; drying the washed microcapsules at a vacuum degree of 30-50kPa and 40-60°C for 4-6h to obtain microencapsulated ultrasonic reflective particles.

2. A gastrointestinal contrast agent according to claim 1, characterized in that: The invention comprises the following raw materials in parts by weight: 70 parts of purified water, 15 parts of chitosan, 12.5 parts of sodium beta-glycerophosphate, 7.5 parts of microencapsulated ultrasound reflective particles, 2 parts of sodium hyaluronate, 0.4 parts of food coloring, and 0.2 parts of antioxidant.

3. A gastrointestinal contrast agent according to claim 1, characterized in that: The food pigment is one of chlorophyll, curcumin, beetroot red, cochineal red, saffron pigment, purple cabbage pigment, and butterfly pea pigment.

4. A gastrointestinal contrast agent according to claim 1, characterized in that: The antioxidant is composed of vitamin C, butylated hydroxytoluene and tea polyphenols in a mass ratio of (3-5):(2-4):(1-3).

5. A gastrointestinal contrast agent according to claim 1, characterized in that: The mass volume ratio of the polyhydroxyalkanoate to chloroform is (1.0-1.5) to (5.0-10.0) g / mL; the mass volume ratio of the nano zinc oxide to the phosphate buffer is (0.1-0.2) to (4.0-10.0) g / mL; the volume ratio of the inner water phase, Span 80, and the polymer solution is (1.0-1.5) to (0.2-0.4) to (3.0-5.0); the volume ratio of the water-in-oil emulsion to the polyvinyl alcohol solution is (1-2) to (6-10).

6. The method for preparing a gastrointestinal contrast agent according to claim 1, characterized in that: The following steps are involved: S1. Weigh the purified water, chitosan, sodium β-glycerophosphate, microencapsulated ultrasound reflective particles, sodium hyaluronate, food coloring, and antioxidant in the above-mentioned portions by weight and set aside; S2, taking one third of pure water, adding chitosan thereto, stirring and dissolving, to obtain a chitosan solution; S3, adding sodium β-glycerophosphate to the chitosan solution, stirring and dissolving, to obtain composite solution I; S4, adding the remaining purified water to the composite solution I, and adding sodium hyaluronate, food coloring, and antioxidant, stirring and dissolving to obtain a composite solution II; S5. Add the microencapsulated ultrasound-reflecting particles into the composite solution II, stir evenly, and place the mixture in a homogenizer for homogenization to obtain a gastrointestinal contrast agent.

7. The method for preparing a gastrointestinal contrast agent according to claim 6, characterized in that: In the S2, the stirring speed is 200-500 r / min and the stirring time is 20-30 min, in the S3, the stirring speed is 200-500 r / min and the stirring time is 5-15 min, in the S4, the stirring speed is 200-500 r / min and the stirring time is 10-20 min, and in the S5, the stirring speed is 100-300 r / min and the stirring time is 5-10 min.

8. The method for preparing a gastrointestinal contrast agent according to claim 6, characterized in that: The homogenization process in S5 is carried out at a homogenization pressure of 20-40 MPa for 5-15 minutes.

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