A microcapsule ultrasound contrast agent and its preparation method

Abstract

The present invention belongs to the technical field of ultrasonic imaging agents, and specifically relates to a microcapsule ultrasonic contrast agent and a preparation method thereof. The method comprises dissolving artemisinin in an organic solvent, dispersing iohexol in the organic solvent, adding bovine serum albumin to obtain an organic solution of iohexol as an oil phase; dissolving λ-carrageenan in hot water as an aqueous phase, mixing and ultrasonicating to obtain a primary oil-in-water emulsion; passing through a membrane, centrifuging, washing with water, and freeze-drying to obtain an ultrasound contrast agent. After accelerated testing, it was verified that the content of related substances of the active ingredient in the contrast agent was significantly reduced, the storage stability was significantly improved, and it was used in clinical practice, meeting higher standards of quality control requirements.

Description

Technical Field

[0001] The present 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] Ultrasound contrast agents, when injected intravenously, enhance the contrast of ultrasound images, distinguishing subtle changes in blood perfusion between normal and diseased tissues and detecting blood flow within small blood vessels in deep tissues and organs. Currently, the most widely used ultrasound contrast agents are gas-containing microvesicles with a diameter of 2 to 8 microns. The shell material can be proteins, lipids, surfactants, sugars, or polymers, and the gas can be carbon dioxide, air, oxygen, or fluorocarbon gases. The gas encapsulated within the microbubbles can alter the scattering and attenuation of ultrasound by tissues and organs, as well as the speed and nonlinear effects of ultrasound propagation in tissues, significantly enhancing their echographic signals and greatly improving diagnostic sensitivity and specificity. This addresses the shortcomings and deficiencies of conventional ultrasound diagnosis and has led to further development in the field of ultrasound diagnosis.

[0003] Chinese patent publication number CN105833302A discloses a contrast agent and a method for preparing the same, comprising, by weight: 2-4 parts of diphenylphosphoryl azide, 8-12 parts of dipalmitoylphosphatidylcholine, 3-5 parts of phospholipid, 2.5-3.5 parts of cholesterol, 1.5-2.5 parts of melanin, and 8-15 parts of perfluoropropane, wherein the phospholipid is a PEGylated phospholipid.

[0004] Chinese patent publication number CN110639032A discloses a high-frequency ultrasound contrast agent comprising a lipid shell and a gas core. The lipid shell comprises a phospholipid, a stabilizer, and sodium alginate. Superparamagnetic particles are attached to the surface of the lipid shell via amide bonds. The phospholipid is one or more of carboxylated DSPC, DPPC, DSPE, DPPE, or DSPE-PEG2000, and the stabilizer is one or more of PEG4000, F68, or PEG40s. However, the problems associated with these ultrasound contrast agents have not been fully addressed.

[0005] Artemisinin, a natural compound extracted from Artemisia annua, is one of the mainstays of malaria treatment. It was originally discovered by Chinese pharmacist Tu Youyou, who won the Nobel Prize in Physiology or Medicine. Artemisinin and its derivatives play a crucial role in the antimalarial field. Artemisinin is a chemical substance containing a lactone ring and belongs to the sesquiterpenoid family. Its unique chemical structure confers high antimalarial activity. Its mechanism of action is to bind to the iron in malarial parasites, forming free radicals that destroy the parasite's cell membrane and ultimately kill the parasite. Artemisinin has a significant antimalarial effect, particularly against drug-resistant malaria. Furthermore, artemisinin's potential antiviral and antitumor effects offer promising research prospects in other fields.

[0006] Hysterosalpingography (HSG) is a commonly used method for screening tubal infertility. This examination can help diagnose and differentiate diseases related to the uterus and fallopian tubes. However, the complication of contrast agent retrograde flow during HSG examinations is common. The contrast agent may enter the myometrium, pelvic cavity, lymphatic system, or blood vessels along an abnormal path, causing central venous retrograde flow, which in turn leads to symptoms such as abdominal pain, nausea and vomiting. In severe cases, it may even cause pulmonary arteriolar embolism, organ failure, or death. Summary of the Invention

[0007] To overcome the deficiencies of the prior art, the present invention provides a microcapsule ultrasound contrast agent and a preparation method thereof. The contrast agent can significantly reduce the phenomenon of reflux characteristics and improve clinical drug safety. At the same time, to address the problem of impurity increase during storage, the present invention improves the quality of various contrast agents including iohexol by adjusting the dosage of active substances and screening excipients.

[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 iohexol organic solution 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, ultrasonication is performed to prepare 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 through a 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: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 includes the following method:

[0020] 1) dissolving artemisinin in ethyl acetate, then dispersing iohexol in the ethyl acetate, and adding 0.1-0.3 parts by weight of bovine serum albumin to obtain an ethyl acetate solution of iohexol as the 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 λ-carrageenan aqueous solution has a mass percentage of 1.5-3.5%;

[0022] 3) mixing the oil phase and the water phase in a volume ratio of 1:20-50, and ultrasonicating at a power of 550 W for 2-4 minutes to prepare an oil-in-water primary emulsion;

[0023] 4) The primary emulsion system obtained in step 3) was poured into a storage tank of a rapid membrane emulsification device, passed through the membrane three times under a nitrogen pressure of 180 kPa, stirred at 60 rpm at room temperature for 24 hours, and the precipitate was collected by centrifugation. The resulting precipitate was washed with water and freeze-dried three times to obtain the product.

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

[0025] 1) dissolving artemisinin in ethyl acetate, then dispersing iohexol in the ethyl acetate, and adding 0.2 parts by weight of bovine serum albumin to obtain an iohexol solution as the 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 30° C. hot water to obtain a stabilizer aqueous solution as the aqueous phase; the mass percentage of the λ-carrageenan aqueous solution is 2.5%;

[0027] 3) mixing the oil phase and the water phase in a volume ratio of 1:30, and ultrasonicating at a power of 550 W for 2-4 minutes to prepare an oil-in-water primary emulsion;

[0028] 4) The primary emulsion system obtained in step 3) was poured into a storage tank of a rapid membrane emulsification device, passed through the membrane three times under a nitrogen pressure of 180 kPa, stirred at 60 rpm at room temperature for 24 hours, and the precipitate was collected by centrifugation. The resulting precipitate was washed with water and freeze-dried 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-type ultrasound contrast agent that significantly improves its clinical efficacy by incorporating artemisinin, particularly in reducing reflux. The inventors speculate that the microcapsule particle size is larger than that of the liquid molecules, effectively preventing some iohexol from flowing back. Furthermore, the addition of substances such as λ-carrageenan further stabilizes the microcapsule structure by strengthening the molecular forces between the microcapsules, reducing the possibility of reflux. Accelerated testing has demonstrated that the content of iohexol-related substances in the contrast agent is significantly reduced, significantly improving storage stability, and thus effectively extending the product's shelf life.

[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 exceeded 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, because 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

[0033] Figure 1 : Detection of the maximum single impurity content of iohexol in an accelerated test at 0, 1, 2, 3, and 6 months.

[0034] Figure 2 : Accelerated test for detection of total impurities in iohexol at 0, 1, 2, 3, and 6 months.

[0035] Figure 3 : Images taken in the early stage of angiography using Example 3 of the present invention.

[0036] Figure 4 : The image at the peak of angiography using Example 3 of the present invention. DETAILED DESCRIPTION

[0037] In order to make the purpose and technical solution of the present invention more clear, the present invention is further described below in conjunction with the embodiments, but the scope of protection of the present invention is not limited to these embodiments, and the embodiments are only used to illustrate 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 scope of protection of the present invention.

[0038] Example 1: A capsule-type ultrasound contrast agent, comprising the following ingredients:

[0039] 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 the oil phase; λ-carrageenan is dissolved in hot water at 20-40°C to obtain a stabilizer aqueous solution as the water phase; the mass percentage of the λ-carrageenan aqueous solution is 1.5%; the oil phase and the water phase are mixed in a volume ratio of 1:20, and ultrasonicated at a power of 550W for 2 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 three times under a nitrogen pressure of 180 kPa, stirred at 60 rpm at room temperature for 24 hours, and the precipitate is collected by centrifugation. The obtained precipitate is washed with water and freeze-dried three times to obtain a capsule-type ultrasound contrast agent containing iohexol.

[0040] Example 2: A capsule-type ultrasound contrast agent, comprising the following ingredients:

[0041] 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 the oil phase; λ-carrageenan is dissolved in 40°C hot water to obtain a stabilizer aqueous solution as the water phase, and the mass percentage of the λ-carrageenan aqueous solution is 3.5%; the oil phase and the water 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 emulsion is passed through a membrane three times under a nitrogen pressure of 180 kPa, stirred at 60 rpm at room temperature for 24 hours, and the precipitate is collected by centrifugation. The obtained precipitate is washed with water and freeze-dried three times to obtain a capsule-type ultrasound contrast agent containing iohexol.

[0042] Example 3: A capsule-type ultrasound contrast agent, comprising the following ingredients

[0043] 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 the oil phase; λ-carrageenan is dissolved in 30°C hot water 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 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 three times under a nitrogen pressure of 180 kPa, stirred at 60 rpm at room temperature for 24 hours, and the precipitate is collected by centrifugation. The obtained precipitate is washed with water and freeze-dried three times to obtain a capsule-type ultrasound contrast agent containing iohexol.

[0044] Example 4: A capsule-type ultrasound contrast agent, comprising the following ingredients

[0045] 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 the oil phase; λ-carrageenan is dissolved in 30°C hot water 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 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 three times under a nitrogen pressure of 180 kPa, stirred at 60 rpm at room temperature for 24 hours, and the precipitate is collected by centrifugation. The obtained precipitate is washed with water and freeze-dried three times to obtain a capsule-type ultrasound contrast agent containing iohexol.

[0046] Comparative Example 1: A capsule-type ultrasound contrast agent, the contrast agent containing the following ingredients

[0047] 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 the oil phase; λ-carrageenan is dissolved in 30° C. hot water 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 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, passed through a membrane three times under a nitrogen pressure of 180 kPa, stirred at 60 rpm at room temperature for 24 hours, and the precipitate is collected by centrifugation. The obtained precipitate is washed with water and freeze-dried three times to obtain a capsule-type ultrasound contrast agent containing iohexol.

[0048] Comparative Example 2: A capsule-type ultrasound contrast agent, the contrast agent containing the following ingredients

[0049] 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 the oil phase; λ-carrageenan is dissolved in 30°C hot water 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 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 three times under a nitrogen pressure of 180 kPa, stirred at 60 rpm at room temperature for 24 hours, and the precipitate is collected by centrifugation. The obtained precipitate is washed with water and freeze-dried three times to obtain a capsule-type ultrasound contrast agent containing iohexol.

[0050] Comparative Example 3: A capsule-type ultrasound contrast agent, the contrast agent containing the following ingredients

[0051] 5 g of artemisinin is dissolved in 567 ml of ethyl acetate solution, and then 350 g of iohexol is dispersed in the solution as the oil phase; λ-carrageenan is dissolved in 30° C. hot water 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 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, passed through a membrane three times under a nitrogen pressure of 180 kPa, stirred at 60 rpm at room temperature for 24 hours, and the precipitate is collected by centrifugation. The obtained precipitate is washed with water and freeze-dried three times to obtain a capsule-type ultrasound contrast agent containing iohexol.

[0052] Comparative Example 4: A capsule-type ultrasound contrast agent, the contrast agent containing the following ingredients

[0053] 0.2 g of bovine serum albumin and 21 g of artemisinin were dissolved in 567 ml of ethyl acetate solution as the oil phase; λ-carrageenan was dissolved in 30° C. hot water and 350 g of iohexol was added to obtain a stabilizer aqueous solution as the water phase; the mass percentage of the λ-carrageenan aqueous solution was 2.5%; the oil phase and the water phase were 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 was poured into a storage tank of a rapid membrane emulsification device, passed through a membrane three times under a nitrogen pressure of 180 kPa, stirred at 60 rpm at room temperature for 24 hours, and the precipitate was collected by centrifugation. The obtained precipitate was washed with water and freeze-dried three times to obtain a capsule-type ultrasound contrast agent containing iohexol.

[0054] Verification Example 1: Detection of Related Substances

[0055] 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 approximately 20 minutes. The detection wavelength was 254 nm.

[0056] Table 1

[0057]

[0058] Preparation of test solution: Take an 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, which is used as the test solution.

[0059] Preparation of reference solution: Take appropriate amount of 5-acetylamino-N, N'-bis-(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide (impurity II) reference substance and 5-nitro-N, N'-bis-(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (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).

[0060] System suitability solution: Weigh 37.5 mg of iohexol reference substance and place it in a 25 ml volumetric flask. Add 1.0 ml each of reference substance solution (1) and reference substance solution (2). Dilute to the mark with water and shake well. Take 20 μl of the system suitability solution as the system suitability solution and inject it into the liquid chromatograph. The order of peaks 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 it 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 between 0.84 and 1.0 times the retention time of the iohexol internal isomer peak, other impurities are calculated by peak area normalization method.

[0061] Accelerated test: Temperature condition is 40℃±2℃, relative humidity 75%±5%, and the above-mentioned related substances are tested at 0, 1, 2, 3 and 6 months.

[0062] 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 were below 0.05%, while the contents of other Examples exceeded 0.1% as time went by, which did not meet the requirements of the Pharmacopoeia.

[0063] Figure 2 Accelerated testing of the total impurity content in iohexol at 0, 1, 2, 3, and 6 months showed that the related substances in Examples 1-3 were around 0.1%, while the total impurity content in other Examples exceeded 0.2% as time went by.

[0064] Verification Example 2: Detection of Clinical Efficacy

[0065] Clinical data of 226 infertile patients who underwent HSG examination at 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 accompanied by 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 accompanied by 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 31 patients who used the iohexol of Comparative Example 1 as a fallopian tube contrast agent. In 39 cases where the iohexol of Example 3 was used as a fallopian tube contrast agent, there were 3 cases of reflux, and in 30 cases where the iohexol of Comparative Example 1 was used as a fallopian tube contrast agent, there were 5 cases of reflux; among the 58 patients with infertility accompanied by endometrial damage, 24 cases used commercially available iohexol as a fallopian tube contrast agent, there were 5 cases of reflux, 24 cases used the iohexol of Example 3 as a fallopian tube contrast agent, there were 2 cases of reflux, and 10 cases used the iohexol of Comparative Example 1 as a fallopian tube contrast agent, there were 2 cases of reflux.

[0066] Figure 3 : Images taken in the early stage of angiography using Example 3 of the present invention.

[0067] 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 the 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, ultrasonication is performed to prepare an oil-in-water primary emulsion; 4) pouring the primary emulsion system obtained in step 3) into a storage tank of a rapid membrane emulsification device, passing the membrane under nitrogen pressure, stirring at room temperature, centrifuging, washing with water, and freeze-drying for times to obtain; Wherein, the organic solvent is selected from ethyl acetate.

2. The ultrasound contrast agent according to claim 1, characterized in that 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.

3. 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%.

4. The ultrasound contrast agent according to claim 1, characterized in that 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 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.

6. The ultrasound contrast agent according to claim 1, characterized in that 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.

7. 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.

8. The ultrasound contrast agent according to claim 1, characterized in that The volume ratio of the oil phase to the water phase is 1:

30.

9. 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 the ethyl acetate, and adding 0.1-0.3 parts by weight of bovine serum albumin to obtain an ethyl acetate solution of iohexol as the 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 λ-carrageenan aqueous solution has a mass percentage of 1.5-3.5%; 3) After mixing the oil phase and the water phase in a volume ratio of 1:20-50, ultrasonically treat the mixture at a power of 550W for 2-4 minutes to prepare an oil-in-water primary emulsion; 4) The primary emulsion system obtained in step 3) was poured into a storage tank of a rapid membrane emulsification device, passed through a membrane three times under a nitrogen pressure of 180 kPa, stirred at 60 rpm at room temperature for 24 hours, and the precipitate was collected by centrifugation. The resulting precipitate was washed with water and freeze-dried three times to obtain the product.

10. 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 the ethyl acetate, and adding 0.2 parts by weight of bovine serum albumin to obtain an iohexol solution as the 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 30° C. hot water to obtain a stabilizer aqueous solution as the aqueous phase; the λ-carrageenan aqueous solution has a mass percentage of 2.5%; 3) After mixing the oil phase and the water phase in a volume ratio of 1:30, ultrasonically treat the mixture at a power of 550 W for 2-4 minutes to prepare an oil-in-water primary emulsion; 4) The primary emulsion system obtained in step 3) was poured into a storage tank of a rapid membrane emulsification device, passed through a membrane three times under a nitrogen pressure of 180 kPa, stirred at 60 rpm at room temperature for 24 hours, and the precipitate was collected by centrifugation. The resulting precipitate was washed with water and freeze-dried three times to obtain the product.

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

Images