Microcapsule ultrasonic contrast agent and preparation method thereof

Abstract

The invention belongs to the technical field of ultrasonic imaging agents, and particularly relates to a micro-capsule ultrasonic contrast agent and a preparation method thereof. The method comprises the following steps: dissolving arteolide in an organic solvent, then dispersing iohexol in the organic solvent, and adding bovine serum albumin to obtain an organic solution of iohexol as an oil phase; lambda-carrageenan is dissolved in hot water to serve as a water phase, ultrasonic treatment is conducted after mixing, and an oil-in-water primary emulsion is prepared; and filtering through a membrane, centrifuging, washing with water, and freeze-drying to obtain the product. Acceleration tests prove that the content of related substances of active ingredients in the contrast agent is remarkably reduced, the storage stability is remarkably improved, and the contrast agent is clinically used and meets the higher-standard quality control requirement.

Description

Technical Field

[0001] The invention belongs to the technical field of ultrasonic imaging agents, and in particular relates to a microcapsule ultrasonic contrast agent and a preparation method thereof. Background Art

[0002] After being injected intravenously into the body, ultrasound contrast agents can enhance the contrast of ultrasound images, distinguish subtle changes in blood perfusion between normal and diseased tissues, and detect blood flow in small blood vessels in deep tissues and organs of the body. Currently, the most widely used ultrasound contrast agents usually refer to microvesicles with a diameter of 2 to 8 microns containing gas. The shell material can be protein, lipid, surfactant, sugar or polymer, and the gas can be carbon dioxide, air, oxygen and fluorocarbon gas. The gas wrapped inside the microbubble can change the scattering and attenuation of ultrasound by tissues and organs, as well as the propagation speed and nonlinear effect of ultrasound in tissues, significantly enhance its echo image signal, greatly improve the sensitivity and specificity of diagnosis, make up for the defects and deficiencies of conventional ultrasound diagnosis, and make greater progress in the field of ultrasound diagnosis.

[0003] A Chinese patent with publication number CN105833302A discloses a contrast agent and a method for preparing the same, which comprises, by weight: 2 to 4 parts of diphenylphosphoryl azide, 8 to 12 parts of dipalmitoylphosphatidylcholine, 3 to 5 parts of phospholipids, 2.5 to 3.5 parts of cholesterol, 1.5 to 2.5 parts of melanin and 8 to 15 parts of perfluoropropane, wherein the phospholipids are PEGylated phospholipids.

[0004] A Chinese patent with publication number CN110639032A discloses a high-frequency ultrasound contrast agent, which is composed of a lipid shell and a gas core, wherein the lipid shell is composed of phospholipids, a stabilizer and sodium alginate, and superparamagnetic particles are connected to the surface of the lipid shell through amide bonds, wherein the phospholipids are one or more of carboxylated DSPC, DPPC, DSPE, DPPE, and DSPE-PEG2000, and the stabilizer is one or more of PEG4000, F68, and PEG40s. However, the problems of the above ultrasound contrast agents have not been well solved.

[0005] Artemisinin is a natural compound extracted from Artemisia annua and is one of the main drugs for treating malaria. It was originally discovered by Chinese pharmacist Tu Youyou, who won the Nobel Prize in Physiology or Medicine. Artemisinin and its derivatives play an extremely important role in the field of anti-malarial. Artemisinin is a chemical substance containing a lactone ring and belongs to the sesquiterpenoid class of compounds. It has a unique chemical structure and has high anti-malarial activity. Its mechanism of action is to bind to the iron in malarial parasites to form free radicals, destroy the cell membrane of malarial parasites, and then kill malarial parasites. Artemisinin has a very significant anti-malarial effect, especially for drug-resistant malaria. In addition, the potential antiviral and anti-tumor effects of artemisinin provide broad prospects for its research in other fields.

[0006] A common method for screening tubal infertility is hysterosalpingography (HSG), which can help diagnose and differentiate diseases related to the uterus and fallopian tubes. However, the complication of contrast medium reflux often occurs during HSG examination. The contrast medium may enter the uterine muscle layer, pelvic cavity, lymphatic system or blood vessels along an abnormal path, causing central venous reflux, which in turn causes abdominal pain, nausea and vomiting in patients. In severe cases, it may even cause pulmonary arteriolar embolism, organ failure or death. Summary of the invention

[0007] In order to overcome the deficiencies of the prior art, the present invention provides a microcapsule ultrasound contrast agent and a preparation method thereof, wherein the contrast agent can significantly reduce the phenomenon of reflux characteristics and improve clinical drug safety; at the same time, in order to solve the problem of impurity increase during storage, the present invention improves the quality of various contrast agents including iohexol by using active substance dosage and screening of auxiliary materials.

[0008] Specifically, the technical solution of the present invention is as follows.

[0009] The present invention provides a microcapsule ultrasound contrast agent, the preparation of which comprises the following method:

[0010] 1) dissolving artemisinin in an organic solvent, then dispersing iohexol in the organic solvent, and adding bovine serum albumin to obtain an organic solution of iohexol as an oil phase; wherein the weight ratio of iohexol to artemisinin is 5:0.1-0.5, and the weight volume ratio of artemisinin to the organic solvent is 1:20.7-35.5;

[0011] 2) dissolving λ-carrageenan in hot water at 20-40° C. to obtain a stabilizer aqueous solution as the aqueous phase; the mass percentage of the λ-carrageenan aqueous solution is 1.5-3.5%;

[0012] 3) After the oil phase and the water phase are mixed, ultrasonic treatment is performed to obtain an oil-in-water primary emulsion;

[0013] 4) Pour the primary emulsion system obtained in step 3) into a storage tank of a rapid membrane emulsification device, pass the membrane under nitrogen pressure, stir at room temperature, centrifuge, wash with water, and freeze-dry for times to obtain.

[0014] Furthermore, in a preferred embodiment of the invention, the weight ratio of iohexol to artemisinin is 5:0.3, and the weight volume ratio of artemisinin to the organic solvent is 1:27.

[0015] Furthermore, the organic solvent is selected from any one of DMSO, ether and ethyl acetate.

[0016] Furthermore, in a preferred embodiment of the invention, the organic solvent is selected from ethyl acetate.

[0017] Furthermore, the mass percentage of the λ-carrageenan aqueous solution is 2.5%

[0018] Furthermore, the volume ratio of the oil phase to the water phase is 1:30.

[0019] Furthermore, the preparation of the ultrasound contrast agent comprises the following method:

[0020] 1) dissolving artemisinin in ethyl acetate, then dispersing iohexol in ethyl acetate, and adding 0.1-0.3 parts by weight of bovine serum albumin to obtain an ethyl acetate solution of iohexol as an oil phase; wherein the weight ratio of iohexol to artemisinin is 5:0.3, and the weight volume ratio of artemisinin to the organic solvent is 1:27;

[0021] 2) dissolving λ-carrageenan in hot water at 20-40° C. to obtain a stabilizer aqueous solution as the aqueous phase; the mass percentage of the λ-carrageenan aqueous solution is 1.5-3.5%;

[0022] 3) After the oil phase and the water phase are mixed in a volume ratio of 1:20-50, ultrasonic treatment is performed at a power of 550 W for 2-4 minutes to obtain an oil-in-water primary emulsion;

[0023] 4) Pour the primary emulsion system obtained in step 3) into a storage tank of a rapid membrane emulsification device, pass through the membrane three times under a nitrogen pressure of 180 kPa, stir at 60 rpm at room temperature for 24 hours, collect the precipitate by centrifugation, and repeat the washing and freeze-drying three times to obtain the product.

[0024] Furthermore, the preparation of the ultrasound contrast agent comprises the following method:

[0025] 1) dissolving artemisinin in ethyl acetate, then dispersing iohexol in ethyl acetate, and adding 0.2 parts by weight of bovine serum albumin to obtain an iohexol solution as an oil phase; wherein the weight ratio of iohexol to artemisinin is 5:0.3, and the weight volume ratio of artemisinin to the organic solvent is 1:27;

[0026] 2) dissolving λ-carrageenan in hot water at 30° C. to obtain a stabilizer aqueous solution as the aqueous phase; the mass percentage of the λ-carrageenan aqueous solution is 2.5%;

[0027] 3) After the oil phase and the water phase are mixed in a volume ratio of 1:30, ultrasonic treatment is performed at a power of 550 W for 2-4 minutes to obtain an oil-in-water primary emulsion;

[0028] 4) Pour the primary emulsion system obtained in step 3) into a storage tank of a rapid membrane emulsification device, pass through the membrane three times under a nitrogen pressure of 180 kPa, stir at 60 rpm at room temperature for 24 hours, collect the precipitate by centrifugation, and repeat the washing and freeze-drying three times to obtain the product.

[0029] The ultrasonic contrast agent of the present invention is used in hysterosalpingography.

[0030] Compared with the prior art, the technical effects of the present invention are:

[0031] 1) The present invention provides a capsule ultrasound contrast agent, which significantly improves its clinical application effect by adding artemisinin, especially in reducing the backflow phenomenon. The inventor speculates that the particle size of the microcapsule is larger than the particle size of the liquid molecule, which can effectively prevent the partial backflow of iohexol; in addition, the added substances such as λ-carrageenan further stabilize the microcapsule structure by enhancing the molecular force between the microcapsules, thereby reducing the possibility of backflow. After accelerated test verification, it was found that the content of iohexol-related substances in the contrast agent was significantly reduced, and the storage stability was significantly improved, thereby effectively extending the shelf life of the product.

[0032] 2) After a 6-month accelerated test, the results showed that the content of iohexol-related substances in the capsule ultrasound contrast agent of the present invention was significantly reduced, which is better than the requirements of the 2020 edition of the Chinese Pharmacopoeia for the content of related substances. This finding shows that the contrast agent exhibits good stability during long-term storage, effectively prolongs the storage time, and ensures its safety and effectiveness in clinical applications. At the same time, since the stability of the product has been greatly improved, the quality fluctuations that may occur during production and storage are greatly reduced, meeting higher standards of quality control requirements. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 : Accelerated test for the detection of the maximum single impurity content of iohexol at 0, 1, 2, 3, and 6 months. Figure 2 : Accelerated test for detection of total impurities in iohexol at 0, 1, 2, 3, and 6 months. Figure 3 : Images taken in the early stage of angiography using Example 3 of the present invention. Figure 4 : The image at the peak of angiography using Example 3 of the present invention. DETAILED DESCRIPTION

[0033] In order to make the purpose and technical solution of the present invention clearer, the present invention is further described below in conjunction with embodiments, but the protection scope of the present invention is not limited to these embodiments, and the embodiments are only used to explain the present invention. It should be understood by those skilled in the art that any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0034] Example 1: A capsule-type ultrasound contrast agent, the contrast agent comprising the following ingredients

[0035] 7g of artemisinin is dissolved in 144.9ml of ethyl acetate solution, and then 350g of iohexol is dispersed in the solution, and 0.1g of bovine serum albumin is added to obtain an iohexol solution as an oil phase; λ-carrageenan is dissolved in hot water at 20-40°C to obtain a stabilizer aqueous solution as an aqueous phase; the mass percentage of the λ-carrageenan aqueous solution is 1.5%; the oil phase and the aqueous phase are mixed in a volume ratio of 1:20, and ultrasonicated at a power of 550W for 2min to obtain an oil-in-water primary emulsion; the obtained primary emulsion system is poured into a storage tank of a rapid membrane emulsification device, and the membrane is passed for 3 times under a nitrogen pressure of 180 kPa, and stirred at 60rpm for 24 hours at room temperature, and the precipitate is collected by centrifugation, and the obtained water washing and freeze-drying are repeated 3 times to obtain a capsule ultrasonic contrast agent containing iohexol.

[0036] Example 2: A capsule-type ultrasound contrast agent, the contrast agent containing the following ingredients

[0037] 35g of artemisinin is dissolved in 1242.5ml of ethyl acetate solution, and then 350g of iohexol is dispersed in the solution, and 0.3g of bovine serum albumin is added to obtain an iohexol solution as an oil phase; λ-carrageenan is dissolved in 40°C hot water to obtain a stabilizer aqueous solution as an aqueous phase, and the mass percentage of the λ-carrageenan aqueous solution is 3.5%; the oil phase and the aqueous phase are mixed in a volume ratio of 1:50, and ultrasonicated at a power of 550W for 4 minutes to obtain an oil-in-water primary emulsion; the obtained primary emulsion system is poured into a storage tank of a rapid membrane emulsification device, and the membrane is passed for 3 times under a nitrogen pressure of 180 kPa, and stirred at 60rpm for 24 hours at room temperature, and the precipitate is collected by centrifugation. The obtained water washing and freeze-drying are repeated for 3 times to obtain a capsule ultrasonic contrast agent containing iohexol.

[0038] Example 3: A capsule ultrasound contrast agent, the contrast agent containing the following ingredients

[0039] 21g of artemisinin is dissolved in 567ml of ethyl acetate solution, and then 350g of iohexol is dispersed in the solution, and 0.2g of bovine serum albumin is added to obtain an iohexol solution as an oil phase; λ-carrageenan is dissolved in 30°C hot water to obtain a stabilizer aqueous solution as an aqueous phase; the mass percentage of the λ-carrageenan aqueous solution is 2.5%; the oil phase and the aqueous phase are mixed in a volume ratio of 1:30, and ultrasonicated at a power of 550W for 3min to obtain an oil-in-water primary emulsion; the obtained primary emulsion system is poured into a storage tank of a rapid membrane emulsification device, and the membrane is passed for 3 times under a nitrogen pressure of 180 kPa, and stirred at 60rpm for 24 hours at room temperature, and the precipitate is collected by centrifugation. The obtained water washing and freeze-drying are repeated for 3 times to obtain a capsule ultrasonic contrast agent containing iohexol.

[0040] Example 4: A capsule ultrasound contrast agent, the contrast agent containing the following ingredients

[0041] 21g of artemisinin is dissolved in 567ml of DMSO solution, and then 350g of iohexol is dispersed in the solution, and 0.2g of bovine serum albumin is added to obtain an iohexol solution as an oil phase; λ-carrageenan is dissolved in 30°C hot water to obtain a stabilizer aqueous solution as an aqueous phase; the mass percentage of the λ-carrageenan aqueous solution is 2.5%; the oil phase and the aqueous phase are mixed in a volume ratio of 1:30, and ultrasonicated at a power of 550W for 3min to obtain an oil-in-water primary emulsion; the obtained primary emulsion system is poured into a storage tank of a rapid membrane emulsification device, and the membrane is passed for 3 times under a nitrogen pressure of 180 kPa, and stirred at 60rpm for 24 hours at room temperature, and the precipitate is collected by centrifugation, and the obtained water washing and freeze-drying are repeated 3 times to obtain a capsule ultrasonic contrast agent containing iohexol.

[0042] Comparative Example 1: A capsule-type ultrasound contrast agent, the contrast agent containing the following ingredients

[0043] Iohexol is dispersed in 567 ml of ethyl acetate solution, and 0.2 g of bovine serum albumin is added to obtain an iohexol solution as an oil phase; λ-carrageenan is dissolved in 30° C. hot water to obtain a stabilizer aqueous solution as an aqueous phase; the mass percentage of the λ-carrageenan aqueous solution is 2.5%; the oil phase and the aqueous phase are mixed in a volume ratio of 1:30, and ultrasonicated at a power of 550 W for 3 minutes to obtain an oil-in-water primary emulsion; the obtained primary emulsion system is poured into a storage tank of a rapid membrane emulsification device, and the membrane is passed for 3 times under a nitrogen pressure of 180 kPa, and stirred at 60 rpm for 24 hours at room temperature, and the precipitate is collected by centrifugation, and the obtained water washing and freeze-drying are repeated 3 times to obtain a capsule ultrasound contrast agent containing iohexol.

[0044] Comparative Example 2: A capsule ultrasound contrast agent, the contrast agent containing the following ingredients

[0045] 21g of artemisinin is dissolved in 567ml of dichloromethane solution, and then 350g of iohexol is dispersed in the solution, and 0.2g of bovine serum albumin is added to obtain an iohexol solution as an oil phase; λ-carrageenan is dissolved in 30°C hot water to obtain a stabilizer aqueous solution as an aqueous phase; the mass percentage of the λ-carrageenan aqueous solution is 2.5%; the oil phase and the aqueous phase are mixed in a volume ratio of 1:30, and ultrasonicated at a power of 550W for 3min to obtain an oil-in-water primary emulsion; the obtained primary emulsion system is poured into a storage tank of a rapid membrane emulsification device, and the membrane is passed for 3 times under a nitrogen pressure of 180 kPa, and stirred at 60rpm for 24 hours at room temperature, and the precipitate is collected by centrifugation, and the obtained water washing and freeze-drying are repeated for 3 times to obtain a capsule ultrasonic contrast agent containing iohexol.

[0046] Comparative Example 3: A capsule ultrasound contrast agent, the contrast agent containing the following ingredients

[0047] 5g of artemisinin is dissolved in 567ml of ethyl acetate solution, and then 350g of iohexol is dispersed in the solution as an oil phase; λ-carrageenan is dissolved in 30°C hot water to obtain a stabilizer aqueous solution as an aqueous phase; the mass percentage of the λ-carrageenan aqueous solution is 2.5%; the oil phase and the aqueous phase are mixed in a volume ratio of 1:30, and ultrasonicated at a power of 550W for 3 minutes to obtain an oil-in-water primary emulsion; the obtained primary emulsion system is poured into a storage tank of a rapid membrane emulsification device, passed through a membrane for 3 times under a nitrogen pressure of 180 kPa, stirred at 60rpm for 24 hours at room temperature, and centrifuged to collect the precipitate. The obtained water washing and freeze-drying are repeated 3 times to obtain a capsule ultrasound contrast agent containing iohexol.

[0048] Comparative Example 4: A capsule-type ultrasound contrast agent, the contrast agent containing the following ingredients

[0049] 0.2g of bovine serum albumin and 21g of artemisinin are dissolved in 567ml of ethyl acetate solution as the oil phase; λ-carrageenan is dissolved in 30°C hot water and 350g of iohexol is added to obtain a stabilizer aqueous solution as the water phase; the mass percentage of the λ-carrageenan aqueous solution is 2.5%; the oil phase and the water phase are mixed in a volume ratio of 1:30, and ultrasonicated at a power of 550W for 3min to obtain an oil-in-water primary emulsion; the obtained primary emulsion system is poured into a storage tank of a rapid membrane emulsification device, passed through a membrane for 3 times under a nitrogen pressure of 180 kPa, stirred at 60rpm for 24 hours at room temperature, and the precipitate is collected by centrifugation. The obtained precipitate is washed with water and freeze-dried for 3 times to obtain a capsule ultrasound contrast agent containing iohexol.

[0050] Verification Example 1: Detection of Related Substances

[0051] According to the high performance liquid chromatography method (General Rule 0512), octadecylsilane bonded silica gel was used as the filler, acetonitrile was used as the mobile phase A, and water was used as the mobile phase B. Gradient elution was performed according to the table below. The flow rate was adjusted so that the retention time of the iohexol exo-isomer peak was about 20 minutes. The detection wavelength was 254 nm.

[0052] Table 1

[0053]

[0054] Preparation of test solution: Take appropriate amount of each example of this embodiment and dilute with water to prepare a solution containing about 1.5 mg of iohexol (0.70 mg of iodine (I)) per 1 ml as the test solution.

[0055] Preparation of reference solution: Take appropriate amount of 5-acetylamino-N,N'-bis-(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxylate (impurity II) reference substance and 5-nitro-N,N'-bis-(2,3-dihydroxypropyl)-1,3-benzenedicarboxylate (impurity III) reference substance, dissolve them in water and dilute them to make solutions containing 75 μg of each per 1 ml, as reference solution (1) and reference solution (2).

[0056] System suitability solution: Weigh 37.5 mg of iohexol reference substance, place in a 25 ml volumetric flask, add 1.0 ml of reference substance solution (1) and reference substance solution (2), dilute to the mark with water, shake well, and use as system suitability solution. Take 20 μl of system suitability solution and inject into the liquid chromatograph. The peak order is impurity II peak, iohexol internal isomer peak, iohexol external isomer peak, O-alkyl compound peak, impurity III peak. The separation between impurity II peak and impurity III peak should be greater than 20.0. Take 20 μl of the test solution and inject into the liquid chromatograph. Record the chromatogram until the gradient elution program ends. In the chromatogram of the test solution, except for the chromatographic peaks with a retention time between 0.84 and 1.0 times relative to the iohexol internal isomer peak, other impurities are calculated by peak area normalization method.

[0057] Accelerated test: The temperature condition is 40℃±2℃, relative humidity is 75%±5%, and the above-mentioned related substances are tested at 0, 1, 2, 3 and 6 months.

[0058] Figure 1 : The accelerated test detected the maximum single impurity content of iohexol at 0, 1, 2, 3, and 6 months. It can be seen that the related substances in Examples 1-3 are below 0.05%, and the contents of other Examples exceed 0.1% as time goes by, which does not meet the requirements of the Pharmacopoeia.

[0059] Figure 2 : The accelerated test detected the total impurity content in iohexol at 0, 1, 2, 3, and 6 months. It can be seen that the related substances in Examples 1-3 are around 0.1%, and the total impurity content of other Examples exceeds 0.2% as time goes by.

[0060] Verification Example 2: Detection of Clinical Efficacy

[0061] Clinical data of 226 infertile patients who underwent HSG examination in the First Affiliated Hospital of Zhengzhou University from October 2023 to October 2024, among whom the age ranged from 25 to 40 years old, with an average of (29.22±3.18) years old; the average infertility time was (2.98±0.22) years; there were 273 cases in total. Among the 107 patients with infertility and adenomyosis, 8 cases of reflux occurred in 38 patients who used the commercially available iohexol as a fallopian tube contrast agent, 3 cases of reflux occurred in 38 patients who used the iohexol of Example 3 as a fallopian tube contrast agent, and 6 cases of reflux occurred in 31 patients who used the iohexol of Comparative Example 1 as a fallopian tube contrast agent; Among the 108 patients with infertility and endometrial polyps, 8 cases of reflux occurred in 39 patients who used the commercially available iohexol as a fallopian tube contrast agent, and 6 cases of reflux occurred in 39 patients who used the commercially available iohexol as a fallopian tube contrast agent. In 39 cases where the iohexol of Example 3 was used as a fallopian tube contrast agent, 3 cases had reflux, and in 30 cases where the iohexol of Comparative Example 1 was used as a fallopian tube contrast agent, 5 cases had reflux; among the 58 patients with infertility accompanied by endometrial damage, 24 cases where the commercially available iohexol was used as a fallopian tube contrast agent had reflux, 24 cases where the iohexol of Example 3 was used as a fallopian tube contrast agent had reflux, and 10 cases where the iohexol of Comparative Example 1 was used as a fallopian tube contrast agent had reflux.

[0062] Figure 3 : Images taken in the early stage of angiography using Example 3 of the present invention.

[0063] Figure 4 : The image at the peak of angiography using Example 3 of the present invention.

Claims

1. A microcapsule ultrasound contrast agent, characterized in that: The preparation of the ultrasound contrast agent comprises the following method: 1) dissolving artemisinin in an organic solvent, then dispersing iohexol in the organic solvent, and adding bovine serum albumin to obtain an organic solution of iohexol as an oil phase; 2) dissolving λ-carrageenan in hot water at 20-40° C. to obtain a stabilizer aqueous solution as the aqueous phase; 3) After the oil phase and the water phase are mixed, ultrasonic treatment is performed to obtain an oil-in-water primary emulsion; 4) Pour the primary emulsion system obtained in step 3) into a storage tank of a rapid membrane emulsification device, pass the membrane under nitrogen pressure, stir at room temperature, centrifuge, wash with water, and freeze-dry for times to obtain.

2. The ultrasound contrast agent according to claim 1, characterized in that The weight dosage ratio of iohexol to artemisinin is 5:0.3, and the weight volume ratio of artemisinin to the organic solvent is 1:

27.

3. The ultrasound contrast agent according to claim 1, characterized in that The organic solvent is selected from any one of DMSO, ether and ethyl acetate, and preferably, the organic solvent is selected from ethyl acetate.

4. The ultrasound contrast agent according to claim 1, characterized in that The mass percentage of the λ-carrageenan aqueous solution is 1.5-3.5%, and preferably, the mass percentage of the λ-carrageenan aqueous solution is 2.5%.

5. The ultrasound contrast agent according to claim 1, characterized in that: The weight dosage ratio of iohexol: artemisinin is 5:0.1-0.5, and the weight volume ratio of artemisinin to organic solvent is 1:20.7-35.

5. Preferably, the weight dosage ratio of iohexol: artemisinin is 5:0.3, and the weight volume ratio of artemisinin to organic solvent is 1:

27.

6. The ultrasound contrast agent according to claim 1, characterized in that The volume ratio of the oil phase to the water phase is 1:20-50, preferably, the volume ratio of the oil phase to the water phase is 1:

30.

7. The ultrasound contrast agent according to claim 1, characterized in that The preparation of the ultrasound contrast agent comprises the following method: 1) dissolving artemisinin in ethyl acetate, then dispersing iohexol in ethyl acetate, and adding 0.1-0.3 parts by weight of bovine serum albumin to obtain an ethyl acetate solution of iohexol as an oil phase; wherein the weight ratio of iohexol to artemisinin is 5:0.3, and the weight volume ratio of artemisinin to the organic solvent is 1:27; 2) dissolving λ-carrageenan in hot water at 20-40° C. to obtain a stabilizer aqueous solution as the aqueous phase; the mass percentage of the λ-carrageenan aqueous solution is 1.5-3.5%; 3) After the oil phase and the water phase are mixed in a volume ratio of 1:20-50, ultrasonic treatment is performed at a power of 550 W for 2-4 minutes to obtain an oil-in-water primary emulsion; 4) Pour the primary emulsion system obtained in step 3) into a storage tank of a rapid membrane emulsification device, pass through the membrane three times under a nitrogen pressure of 180 kPa, stir at 60 rpm at room temperature for 24 hours, collect the precipitate by centrifugation, and repeat the washing and freeze-drying three times to obtain the product.

8. The ultrasound contrast agent according to claim 1, characterized in that The preparation of the ultrasound contrast agent comprises the following method: 1) dissolving artemisinin in ethyl acetate, then dispersing iohexol in ethyl acetate, and adding 0.2 parts by weight of bovine serum albumin to obtain an iohexol solution as an oil phase; wherein the weight ratio of iohexol to artemisinin is 5:0.3, and the weight volume ratio of artemisinin to the organic solvent is 1:27; 2) dissolving λ-carrageenan in hot water at 30° C. to obtain a stabilizer aqueous solution as the aqueous phase; the mass percentage of the λ-carrageenan aqueous solution is 2.5%; 3) After the oil phase and the water phase are mixed in a volume ratio of 1:30, ultrasonic treatment is performed at a power of 550 W for 2-4 minutes to obtain an oil-in-water primary emulsion; 4) Pour the primary emulsion system obtained in step 3) into a storage tank of a rapid membrane emulsification device, pass through the membrane three times under a nitrogen pressure of 180 kPa, stir at 60 rpm at room temperature for 24 hours, collect the precipitate by centrifugation, and repeat the washing and freeze-drying three times to obtain the product.

9. Use of the ultrasound contrast agent according to any one of claims 1 to 8 in the preparation of a drug for hysterosalpingography.

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