Visible ethanol sclerosing agent composition and use thereof

Abstract

The present disclosure relates to a visible ethanol sclerosing agent composition and the use thereof. The composition comprises absolute ethanol, a contrast agent and a co-solvent, wherein the contrast agent is selected from one or more of iopromide, iohexol and ioversol, and the co-solvent contains no water, is miscible with ethanol, and is selected from one or more of DMSO, NMP and DMF. The absolute ethanol is used for strongly sclerosing the blood vessels, the co-solvent is used for increasing the solubility of the contrast agent in the preparation to obtain a good contrast effect, and the contrast agent is used for tracing ethanol under imaging devices. The composition of the present disclosure has a strong sclerosing capacity and can be used for developing and tracing ethanol under imaging devices during an operation, thereby realizing the visualization effect, simplifying the operation, and greatly improving the safety of operation. The sclerosing agent has readily obtainable raw materials, a simple preparation method and easy production, high stability, and convenient storage.

Description

A visual ethanol hardener composition and its application Technical Field

[0001] The present disclosure relates to the technical field of medical hardener materials, and in particular to a visualized ethanol hardener composition, a preparation method thereof, and applications thereof. Background Art

[0002] Hemangiomas and vascular malformations are common vascular abnormalities, requiring different treatments. With the advancement of imaging technology, imaging combined with interventional therapies, including embolization and sclerotherapy, is playing an increasingly important role in treating non-benign hemangiomas and malformations, and is even becoming the primary treatment.

[0003] Embolization therapy involves occluding the target blood vessel using liquid embolic agents, solid embolic materials, or other materials. Representative solid embolic materials include coils (spring coils) and non-degradable gelatin. While interventional embolization can significantly improve clinical symptoms, its effectiveness is less than satisfactory, primarily manifested by post-embolization recurrence and post-embolization infection. The primary cause of post-embolization recurrence is the formation of new blood vessels and recanalization after embolization. If the endothelial cells of the diseased vessels remain relatively intact after treatment, local hypoxia will cause them to release a series of pro-angiogenic factors, leading to the formation of new blood vessels and recanalization, causing disease recurrence. Therefore, using solid materials to embolize the blood supply vessels not only fails to achieve therapeutic effects, but may also lead to the formation of new blood vessels and recanalization, accelerating disease recurrence. Furthermore, coils and tissue glue are foreign materials, prone to foreign body rejection and infection. Because solid materials have difficulty reaching deep vessels and some small blood vessels, and cannot embolize diffusely diseased vessels, this method of vascular obstruction using solid materials has significant limitations.

[0004] To address the limitations of solid embolic materials, researchers have developed embolic agents that convert from liquid to solid. These agents can reach locations inaccessible to pure solid embolic agents. Representative products of this type include OnyxLES and LavaLES, both marketed for cerebral vascular embolization. Onyx LES is an ethylene-vinyl alcohol copolymer. Its component, EVOH (ethylene-vinyl alcohol copolymer), is dissolved in DMSO (dimethyl sulfoxide) and contains micronized tantalum powder, making it visible under fluoroscopy. During use, Onyx LES is delivered to the target site via a microcatheter under fluoroscopy. The DMSO dissolves in the blood and interstitial fluid, and the EVOH copolymer and suspended tantalum powder precipitate at the embolic site, forming a sponge-like, spatially structured embolic material. Another marketed embolic agent, Lava LES, has a very similar composition to Onyx LES and works in the same way, differing only in the accessories and equipment used.

[0005] Sclerotherapy treats malformed blood vessels by destroying the vascular endothelial cells within the lesion (since the vascular endothelial cells are destroyed, there is no need to worry about the release of pro-angiogenic factors leading to the formation of new blood vessels). In recent years, with the development of interventional radiology, sclerotherapy has become the first choice for treating vascular malformations. Sclerotherapy can effectively treat vascular malformations. Its mechanism of action is mainly to cause damage to vascular endothelial cells through different pathways, causing the target blood vessels to harden and become fibrous cords, which are eventually absorbed by the surrounding tissues, thereby achieving the purpose of improving symptoms, appearance and hemodynamic disorders. Sclerotherapy agents that have been used clinically include ethanol, polidocanol, lauromacrogol, sodium tetradecyl sulfate, and bleomycin. Among them, the hardening effect of ethanol is significantly better than other sclerotherapy agents, and it is currently the sclerotherapy agent with the strongest hardening ability.

[0006] It was reported that anhydrous ethanol was used to sclerotherapy a patient with arteriovenous malformation. The patient had a severe arteriovenous malformation in the thigh. A balloon was used to reduce the blood flow rate, and then 5 ml of anhydrous ethanol was injected. The patient received a total of 5 sclerotherapy injections within a few months. 19 months after the last injection treatment, the patient recovered completely.

[0007] Anhydrous ethanol is a highly aggressive sclerosant. Intravascular injection of anhydrous ethanol damages the vessel wall and denatures red blood cell proteins, leading to vascular sclerosis and thrombosis, thereby sclerosis and occlusion of abnormal vascular masses. Anhydrous ethanol injection can cause direct damage to the vessel wall, endothelial cell cytoplasm degeneration, endothelial cell detachment from the vessel wall, and collapse of the elastic layer within the vessel. Furthermore, anhydrous ethanol damages and aggregates red blood cells, denatures plasma proteins, and leads to acute vascular sclerosis and occlusion, but no full-thickness necrosis of the vessel wall is observed. Furthermore, vasospasm, perivascular necrosis, and red blood cell stagnation within arterioles can promote thrombosis.

[0008] Anhydrous ethanol offers many advantages as a sclerosing agent: ① It is readily available, easy to store, and relatively inexpensive. ② It diffuses extensively within abnormal vascular masses, producing a long-lasting embolic effect after injection. ③ It is metabolized and cleared from the body without causing foreign body rejection. ④ As a low-viscosity liquid embolic agent, anhydrous ethanol scleroembolization can treat deep, small, and diffuse vascular malformations. ⑤ It is currently the most potent sclerosing agent with embolic sclerosing capacity.

[0009] Anhydrous ethanol is currently the most potent sclerosant and offers the best scleroembolic effects. Its superior sclerosing efficacy has been proven. However, due to its highly corrosive nature, anhydrous ethanol also has significant drawbacks. For example, inadvertent entry into normal tissues such as nerves, muscle, or connective tissue, particularly arterial blood supply, can cause irreversible necrosis, thus increasing its risk. Furthermore, its use as a sclerosant requires high skill and experience on the part of the clinician. These risks primarily stem from the lack of traceability of ethanol during vascular injection.

[0010] In 1984, Japanese researchers, concerned about the undetectability of anhydrous ethanol during use, first applied anhydrous ethanol to scleroembolization for venous malformations using a method combining anhydrous ethanol and iodized oil. Anhydrous ethanol and iodized oil were mixed in a 9:1 ratio by vortexing. After angiographic contrast agent was injected to locate the abnormality, the mixed contrast sclerotherapy agent was injected under fluorescence or ultrasound conditions. They used this formulation to treat venous malformations of various types (e.g., intramuscular, intermuscular, and cutaneous) in various locations (including the thigh, calf, forearm, and buttocks), achieving generally good tracing and therapeutic efficacy. In 1986, Park, JH, et al. at Sungkyunkwan University in South Korea prepared a mixture of anhydrous ethanol and iodized oil (Liplodol) for injection into rabbit renal arteries under imaging. They demonstrated that a 50% anhydrous ethanol concentration made the formulation radiopaque (i.e., radiopaque) under imaging, while a 75% anhydrous ethanol concentration was radiolucent (i.e., poor radiopaque). They successfully used a 50% anhydrous ethanol solution to sclerotherapy three patients with high-grade nephroma. The mixed solution can be traced under angiography equipment and is an effective drug for renal artery embolization.

[0011] While the ethanol-lipiodol mixture method allows for tracking during use and also exhibits a hardening effect, this preparation also presents numerous challenges. ① Some researchers have prepared a lipiodol hardener using a ratio of anhydrous ethanol to lipiodol of 5:1, finding that its hardening and embolization efficacy was only 45%, a suboptimal result. ② Due to the incompatibility of lipiodol and ethanol, the resulting lipiodol hardener system is extremely unstable, with the lipiodol and ethanol separating within a short period of time. This requires immediate preparation before clinical administration, making it inconvenient. ③ Also due to the high lipid solubility of lipiodol, the lipiodol and ethanol separate after injection into the blood vessels. Furthermore, since lipiodol has a higher density and viscosity than ethanol, it easily deposits and adheres to the vascular endothelium. This not only fails to prolong the retention of ethanol but also prevents direct contact between ethanol and the vascular endothelium, thus compromising the hardening effect.

[0012] Chinese patent CN 111840265 A discloses an ethanol-based sclerosing agent. The pharmaceutical composition contains ethanol, a water-soluble iodine preparation, and water for injection. The volume percentage of ethanol is 76-98%, the mass-volume ratio of the water-soluble iodine preparation to the composition is 50-300 g / L, the mass-volume ratio of the iodine element in the water-soluble iodine preparation to the composition is 23-139 g / L, and the balance is made up of water for injection. This pharmaceutical composition exhibits excellent embolization efficacy, with an embolization rate exceeding 65%. It is autoradiographic upon intravascular injection, allowing imaging equipment to monitor the injection process, demonstrating excellent tracing effectiveness. Furthermore, in 2002, Chinese researchers mixed anhydrous ethanol with the marketed iopromide contrast agent, Uvisen 370, in a 1:1 ratio. After ligating one rabbit carotid artery (approximately 2-3 cm in length), the mixture was injected under digital silhouette angiography (DSA) for scleroembolization.

[0013] The above two methods solve the problem of being unable to monitor when using ethanol. The results of the embodiment in CN 111840265 A show that the embolic effect increases with the increase of the volume fraction of anhydrous ethanol. When the volume fraction of anhydrous ethanol is 70% and the water is 30%, the embolic effect (embolization rate) is only 25%, while when the volume fraction of anhydrous ethanol reaches 90% and the water is 10%, the embolic effect reaches 90%. It can be found that the hardening embolic ability of ethanol is related to its purity (water content). The introduction of water will greatly affect the hardening ability of ethanol. The composition of Uvixant 370 is iopromide + water for injection. After mixing anhydrous ethanol and Uvixant 370 in a ratio of 1:1, the mixed solution is a 50% ethanol-water solution. This will greatly reduce the hardening effect of ethanol. In order to achieve the therapeutic effect, the dosage of the drug must be increased or the number of treatments must be increased.

[0014] To address the issue of water content in ethanol hardeners reducing their hardening ability, CN 113694020 A discloses a method for preparing a visual anhydrous ethanol-iopromide composite hardening injection. The ethanol hardener prepared by this method is a suspension. Iopromide powder is mixed with an appropriate amount of anhydrous ethanol and stirred until uniformly dispersed to form an iopromide-anhydrous ethanol suspension. Anhydrous ethanol is then added to the suspension to a constant volume, ensuring that the resulting composite hardening injection has an ethanol volume fraction of 99.5% at 15°C and an iopromide content of 0.2-0.8 g / ml.

[0015] This preparation has obvious advantages. It can be clearly developed and the hardening agent is anhydrous ethanol, which has a strong hardening ability. However, its disadvantages are also obvious. This preparation is a suspension and has classic problems of suspensions, such as unstable physical properties and low content uniformity. Since the solubility of iopromide in ethanol is extremely low, only 10 mg / ml (at 25°C), the physical stability of a suspension with such a high content is quite poor, resulting in the need for rapid injection. Otherwise, the content uniformity of the suspension will affect the tracing effect and even the hardening effect. In addition, the suspension is used for injection into blood vessels and has poor safety. Therefore, the preparation form of this drug is not an ideal choice. Summary of the Invention

[0016] In one aspect, the present disclosure provides a visualization ethanol sclerosant composition comprising anhydrous ethanol, a contrast agent, and a co-solvent.

[0017] The total volume fraction of anhydrous ethanol and a co-solvent in the composition is 1, and the contrast agent is dissolved therein to form a homogeneous solution.

[0018] In the composition, the anhydrous ethanol is commonly used in the art, such as injection-grade ethanol.

[0019] In the composition, the volume fraction of ethanol may be 70-95%, preferably 72-93%, 74-91%, 75-90%, 77-88%, 79-86%, 80-85%, 82-84%, more preferably 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, and further preferably 80%.

[0020] In the composition, the cosolvent is an organic solvent acceptable to the human body, which is miscible with ethanol and does not contain water, and is selected from one or more of dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP) and dimethylformamide (DMF), preferably DMSO.

[0021] The present invention increases the solubility of the contrast agent in the system by adding a suitable cosolvent, such as DMSO, DMF, NMP and other organic solvents acceptable to the human body. The cosolvent is miscible with ethanol, does not contain water, and is non-aqueous. Without affecting the hardening effect of ethanol, a sufficiently clear development effect is obtained, making the hardener a homogeneous system. The half-biolethal dose (D50) of these organic solvents acceptable to the human body is generally much smaller than that of anhydrous ethanol. For example, the D50 of DMSO for rats and rabbits is 1.5 times and 2 times that of ethanol, respectively. The proportion of organic solvent in the preparation is much smaller than that of ethanol. In addition, because the anhydrous ethanol "vascular" hardener has a very strong ability to harden and embolize blood vessels, the amount of the overall preparation used in clinical use is relatively small, and the amount of organic solvent used is even smaller, so the use of organic solvents is less toxic. When used clinically with multiple vital signs monitoring equipment, the amount of ethanol used is within the safe range, so the safety of the preparation is also relatively high.

[0022] In the composition, the volume fraction of the co-solvent is 5%-30%, preferably 7-28%, 9-26%, 10-25%, 12-23%, 14-21%, 15-20%, 16-18%, more preferably 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, and further preferably 20%.

[0023] In the composition, the contrast agent is a contrast agent conventionally used in clinical angiography, and the contrast agent may be one or more of iopromide, iohexol, and ioversol, preferably iopromide.

[0024] In the composition, the mass volume ratio of the contrast agent to the composition is 10 mg / ml-344 mg / ml, preferably 18-328 mg / ml, 28-296 mg / ml, 40-245 mg / ml, 53-201 mg / ml, 60-138 mg / ml, 66-80 mg / ml, more preferably 28 mg / ml, 40 mg / ml, 70 mg / ml, 138 mg / ml, 230 mg / ml, 300 mg / ml, and further preferably 67 mg / ml.

[0025] In the composition, the mass volume ratio of iodine element in the contrast agent to the composition is 5 mg / ml-165 mg / ml, preferably 9-158 mg / ml, 13-143 mg / ml, 19-118 mg / ml, 26-97 mg / ml, 29-66 mg / ml, 32-39 mg / ml, more preferably 13 mg / ml, 19 mg / ml, 34 mg / ml, 67 mg / ml, 111 mg / ml, 145 mg / ml, and further preferably 67 mg / ml.

[0026] In another aspect, the present disclosure provides a method for preparing a visual ethanol hardener composition, comprising:

[0027] Mix anhydrous ethanol and co-solvent in a certain volume ratio, add contrast agent, and stir to disperse and fully dissolve the contrast agent.

[0028] The fully dissolved mixed solution is filtered to obtain a homogeneous liquid.

[0029] The filtration can be performed by using a membrane filtration method, preferably an organic membrane filtration method, and the organic membrane can be selected from a 0.22 μm organic membrane.

[0030] In the preparation method, the homogeneous liquid can also be obtained by centrifugation. Preferably, the centrifugation speed is >4000 r / min. After high-speed centrifugation, the supernatant is collected to obtain the homogeneous liquid. The homogeneous liquid can also be obtained by standing. For example, after the fully dissolved mixed solution is allowed to stand for a certain period of time, the supernatant is collected to obtain the homogeneous liquid. The standing time is preferably 4 hours or more, more preferably 5 hours or more, and more preferably 6 hours or more.

[0031] The preparation method further comprises the steps of filling the homogeneous liquid into an ampoule, sealing the ampoule, and sterilizing the ampoule at high temperature.

[0032] The high-temperature sterilization method may be a conventional method in the art, and the temperature of the high-temperature sterilization is preferably 115° C.-121° C., for example, 121° C. The sterilization time is preferably 7-30 min, for example, 15 min.

[0033] The ampoule can be a conventional ampoule in the art, preferably a glass ampoule.

[0034] The composition can also be packaged in several ampoules for storage. The packaging volume of the pharmaceutical composition is not limited, but is preferably 5-15 ml.

[0035] The "room temperature" in the present invention refers to 10°C-30°C.

[0036] The above-mentioned preferred conditions may be combined in any manner without departing from the prior art.

[0037] The reagents and raw materials used in the present invention are all commercially available.

[0038] On the other hand, the present disclosure also provides a composition for use as an ethanol-based sclerosing agent. Specifically, the present disclosure provides the use of the above-mentioned composition in the preparation of an interventional embolization treatment drug for arteriovenous malformations. Clinically, during the treatment of a disease, the pharmaceutical composition of the present disclosure is injected under DSA for treatment. The DSA refers to digital subtraction angiography, which mainly involves injecting contrast agents into the patient's veins and arteries to visualize the blood vessels, so that doctors can judge the disease based on changes in the distribution, morphology, position, etc. of the blood vessels, and can perform interventional treatment through a catheter. Clinically, it can be used for the examination and treatment of cardiovascular vessels, large blood vessels in the chest, blood vessels in the head and neck, abdomen, and limbs. In addition, DSA can also be used for interventional radiotherapy. Beneficial effects:

[0039] 1. The ethanol in the ethanol hardener composition disclosed herein is anhydrous ethanol. Compared with aqueous ethanol hardeners, anhydrous ethanol hardeners have stronger hardening and embolization efficacy. Since the raw materials do not contain water, the use of organic solvents is less toxic, and an appropriate amount of organic solvent can achieve the purpose of dissolution without affecting the hardening effect of ethanol. Ultimately, the hardener can effectively harden and embolize blood vessels while tracing anhydrous ethanol under angiography, which can greatly reduce the difficulty of operation and improve surgical safety.

[0040] 2. The ethanol hardener composition disclosed herein has a strong hardening and embolic effect and can be monitored under imaging equipment, thereby preventing it from accidentally entering normal tissues such as nerves, muscles or connective tissues during use, especially accidentally entering blood supply arteries and causing irreversible damage.

[0041] 3. The ethanol hardener composition is a homogeneous liquid with high stability and no hemolysis. The preparation method is simple and the dosage of each component can be adjusted as needed, making it easy to produce and use. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] In order to more clearly illustrate the technical solutions in the present invention or the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0043] FIG1 shows the results of the hemolysis experiment in Experimental Example 3.

[0044] FIG2 is a diagram showing the effects of anhydrous ethanol, an iopromide anhydrous ethanol saturated solution in Experiment 1 in Experiment 5, and Examples 1-6.

[0045] FIG3 is a diagram showing the effects of Examples 7, 14, 27, 34, 47, and 54 in the angiography experiment 1 of Example 5.

[0046] FIG4 is a photo of a polytetrafluoroethylene tube filled with a composition to simulate a blood vessel in angiography experiment 2 of Experimental Example 6.

[0047] FIG5 is a diagram showing the development effect of the polytetrafluoroethylene tube after encapsulation of the composition under X-ray scanning in the imaging experiment 2 of Experimental Example 6.

[0048] FIG6 is a diagram showing the angiography effect under DSA in angiography experiment 3 of Experimental Example 7.

[0049] FIG7 is a diagram showing the effects of the blood vessels in the legs of normal rats (without sclerosis and embolism).

[0050] Figure 8 shows the effect of vascular sclerosis and embolism in the leg after injection of 0.1 ml of anhydrous ethanol in Experimental Example 9

[0051] FIG9 is a diagram showing the effect of vascular sclerosis and embolism in the leg after injection of 0.1 ml of the "vascular" sclerosant composition prepared in Example 6 in Experimental Example 9.

[0052] FIG10 is a diagram showing the effect of vascular sclerosis and embolism in the leg after injection of 0.1 ml of the "vascular" sclerosant composition prepared in Example 7 in Experimental Example 9.

[0053] FIG11 is a diagram showing the effect of vascular sclerosis and embolism in the leg after injection of 0.1 ml of the "vascular" sclerosant composition prepared in Example 14 in Experimental Example 9. DETAILED DESCRIPTION

[0054] Based on the above contents of the present disclosure, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present disclosure, other various forms of modifications, replacements or changes can be made.

[0055] The present disclosure provides a highly stable, non-aqueous ethanol hardener composition capable of tracing ethanol, i.e., a non-aqueous ethanol hardener composition with the strongest hardening efficacy. This hardener composition is a homogeneous system. Suitable contrast agents are selected for tracing ethanol, such as the clinically commonly used, highly safe, non-ionic iodine contrast agent iopromide. However, due to the low solubility of these contrast agents in anhydrous ethanol, simply dissolving them in anhydrous ethanol for use does not produce clear imaging on imaging instruments such as CT and DSA, resulting in poor tracing. The present disclosure increases the solubility of the contrast agent in the system by adding a suitable cosolvent, such as a human-acceptable organic solvent such as DMSO, DMF, or NMP. These cosolvents are miscible with ethanol, contain no water, and are non-aqueous. This allows for sufficiently clear imaging without affecting the hardening effect of ethanol, thereby making the hardener a homogeneous system. The biolethal dose (D50) of these human-acceptable organic solvents is generally much lower than that of anhydrous ethanol. For example, the D50 of DMSO for rats and rabbits is 1.5 times and 2 times that of ethanol, respectively. The proportion of organic solvents in the preparation is far smaller than that of ethanol. Furthermore, because the anhydrous ethanol "vascular" sclerosant is highly potent in hardening and embolizing blood vessels, the overall dosage of the preparation is relatively small in clinical use, and the amount of organic solvent used is even smaller, resulting in a less toxic solution. When used clinically with multiple vital sign monitoring devices, the amount of ethanol used is within a safe range, thus ensuring a high level of safety.

[0056] Unless otherwise stated, all raw materials used in the present disclosure can be obtained through commercial channels.

[0057] Example 1

[0058] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 25 mg, and the volume fraction of anhydrous ethanol is 95%.

[0059] composition:

[0060] Iopromide 25g

[0061] DMSO 50ml

[0062] 950ml of anhydrous ethanol

[0063] Preparation method: Mix DMSO with 50 ml of anhydrous ethanol at room temperature, add 25 g of iopromide while stirring, then slowly add the remaining amount of anhydrous ethanol and stir until the solution is clear. Filter with a 0.22 μm organic filter membrane to obtain a homogeneous solution, divide it into glass ampoules, seal them, and sterilize them at 121°C for 15 minutes.

[0064] Example 2

[0065] The components and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 40 mg, and the volume fraction of anhydrous ethanol is 90%; the preparation method is the same as that of Example 1.

[0066] composition:

[0067] Iopromide 40g

[0068] DMSO 100ml

[0069] 900ml of anhydrous ethanol

[0070] Example 3

[0071] The components and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 70 mg, and the volume fraction of anhydrous ethanol is 85%; the preparation method is the same as that of Example 1.

[0072] composition:

[0073] Iopromide 70g

[0074] DMSO 150ml

[0075] 850ml of anhydrous ethanol

[0076] Example 4

[0077] The components and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 140 mg, and the volume fraction of anhydrous ethanol is 80%; the preparation method is the same as that of Example 1.

[0078] composition:

[0079] Iopromide 140g

[0080] DMSO 200ml

[0081] 800ml of anhydrous ethanol

[0082] Example 5

[0083] The components and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 230 mg, and the volume fraction of anhydrous ethanol is 75%; the preparation method is the same as that of Example 1.

[0084] composition:

[0085] Iopromide 230g

[0086] DMSO 250ml

[0087] 750ml of anhydrous ethanol

[0088] Example 6

[0089] The components and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 345 mg, and the volume fraction of anhydrous ethanol is 70%; the preparation method is the same as that of Example 1.

[0090] composition:

[0091] Iopromide 345g

[0092] DMSO 300ml

[0093] 700ml of anhydrous ethanol

[0094] Example 7

[0095] The components and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 46 mg, and the volume fraction of anhydrous ethanol is 80%;

[0096] composition:

[0097] Iopromide 46g

[0098] NMP 200ml

[0099] 800ml of anhydrous ethanol

[0100] Preparation method: NMP is first mixed evenly with 50 ml of anhydrous ethanol at room temperature, 46 g of iopromide is added thereto while stirring, and then the remaining amount of anhydrous ethanol is slowly added and stirred until the solution is clear. Stir for 24 hours to obtain a homogeneous solution, which is filtered with a 0.22 μm organic filter membrane to obtain a homogeneous solution. The solution is divided into glass ampoules, sealed, and sterilized at 121°C for 15 minutes.

[0101] Example 8

[0102] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 25 mg, and the volume fraction of anhydrous ethanol is 90%; the preparation method is the same as that of Example 7.

[0103] composition:

[0104] Iopromide 25g

[0105] NMP 100ml

[0106] 900ml of anhydrous ethanol

[0107] Example 9

[0108] The components and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 40 mg, and the volume fraction of anhydrous ethanol is 80%; the preparation method is the same as that of Example 7.

[0109] composition:

[0110] Iopromide 40g

[0111] NMP 200ml

[0112] 800ml of anhydrous ethanol

[0113] Example 10

[0114] The components and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 70 mg, and the volume fraction of anhydrous ethanol is 85%; the preparation method is the same as that of Example 7.

[0115] composition:

[0116] Iopromide 70g

[0117] NMP 150ml

[0118] 850ml of anhydrous ethanol

[0119] Example 11

[0120] The components and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 140 mg, and the volume fraction of anhydrous ethanol is 80%; the preparation method is the same as that of Example 7.

[0121] composition:

[0122] Iopromide 140g

[0123] NMP 200ml

[0124] 800ml of anhydrous ethanol

[0125] Example 12

[0126] The components and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 230 mg, and the volume fraction of anhydrous ethanol is 75%; the preparation method is the same as that of Example 7.

[0127] composition:

[0128] Iopromide 230g

[0129] NMP 250ml

[0130] 750ml of anhydrous ethanol

[0131] Example 13

[0132] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 345 mg, and the volume fraction of anhydrous ethanol is 70%; the preparation method is the same as that of Example 7.

[0133] composition:

[0134] Iopromide 345g

[0135] NMP 300ml

[0136] 700ml of anhydrous ethanol

[0137] Example 14

[0138] The components and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 57 mg, and the volume fraction of anhydrous ethanol is 80%;

[0139] composition:

[0140] Iopromide 57g

[0141] DMF 200ml

[0142] 800ml of anhydrous ethanol

[0143] Preparation method: DMF is first mixed with 50 ml of anhydrous ethanol at room temperature, 57 g of iopromide is added thereto while stirring, and then the remaining amount of anhydrous ethanol is slowly added and stirred until the solution is clear. Stir for 24 hours to obtain a homogeneous solution, filter it with a 0.22 μm organic filter membrane, divide it into glass ampoules, seal them, and sterilize them at 121°C for 15 minutes.

[0144] Example 15

[0145] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 25 mg, and the volume fraction of anhydrous ethanol is 95%; the preparation method is the same as that of Example 14.

[0146] composition:

[0147] Iopromide 25g

[0148] DMF 50ml

[0149] 950ml of anhydrous ethanol

[0150] Example 16

[0151] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 40 mg, and the volume fraction of anhydrous ethanol is 90%; the preparation method is the same as that of Example 14.

[0152] composition:

[0153] Iopromide 40g

[0154] DMF 100ml

[0155] 900ml of anhydrous ethanol

[0156] Example 17

[0157] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 70 mg, and the volume fraction of anhydrous ethanol is 85%; the preparation method is the same as that of Example 14.

[0158] composition:

[0159] Iopromide 70g

[0160] DMF 150ml

[0161] 850ml of anhydrous ethanol

[0162] Example 18

[0163] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 140 mg, and the volume fraction of anhydrous ethanol is 80%; the preparation method is the same as that of Example 14.

[0164] composition:

[0165] Iopromide 140g

[0166] DMF 200ml

[0167] 800ml of anhydrous ethanol

[0168] Example 19

[0169] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 230 mg, and the volume fraction of anhydrous ethanol is 75%; the preparation method is the same as that of Example 14.

[0170] composition:

[0171] Iopromide 230g

[0172] DMF 250ml

[0173] 750ml of anhydrous ethanol

[0174] Example 20

[0175] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 345 mg, and the volume fraction of anhydrous ethanol is 70%; the preparation method is the same as that of Example 14.

[0176] composition:

[0177] Iopromide 345g

[0178] DMF 300ml

[0179] 700ml of anhydrous ethanol

[0180] Example 21

[0181] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 25 mg, and the volume fraction of anhydrous ethanol is 95%.

[0182] composition:

[0183] Iohexol 25g

[0184] DMSO 50ml

[0185] 950ml of anhydrous ethanol

[0186] Preparation method: Mix DMSO with 50 ml of anhydrous ethanol at room temperature, add 25 g of iohexol while stirring, and then slowly add the remaining amount of anhydrous ethanol and stir until the solution is clear. Stir for 24 hours to obtain a homogeneous solution, filter it with a 0.22 μm organic filter membrane, divide it into glass ampoules, seal them, and sterilize them at 121°C for 15 minutes.

[0187] Example 22

[0188] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 40 mg, and the volume fraction of anhydrous ethanol is 90%; the preparation method is the same as that of Example 21.

[0189] composition:

[0190] Iohexol 40g

[0191] DMSO 100ml

[0192] 900ml of anhydrous ethanol

[0193] Example 23

[0194] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 70 mg, and the volume fraction of anhydrous ethanol is 85%; the preparation method is the same as that of Example 21.

[0195] composition:

[0196] Iohexol 70g

[0197] DMSO 150ml

[0198] 850ml of anhydrous ethanol

[0199] Example 24

[0200] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 140 mm2, and the volume fraction of anhydrous ethanol is 80%; the preparation method is the same as that of Example 21.

[0201] composition:

[0202] Iohexol 140g

[0203] DMSO 200ml

[0204] 800ml of anhydrous ethanol

[0205] Example 25

[0206] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 230 mg, and the volume fraction of anhydrous ethanol is 75%; the preparation method is the same as that of Example 21.

[0207] composition:

[0208] Iohexol 230g

[0209] DMSO 250ml

[0210] 750ml of anhydrous ethanol

[0211] Example 26

[0212] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 345 mg, and the volume fraction of anhydrous ethanol is 70%; the preparation method is the same as that of Example 21.

[0213] composition:

[0214] Iohexol 345g

[0215] DMSO 300ml

[0216] 700ml of anhydrous ethanol

[0217] Example 27

[0218] The components and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 46 mg, and the volume fraction of anhydrous ethanol is 80%.

[0219] composition:

[0220] Iohexol 46g

[0221] NMP 200ml

[0222] 800ml of anhydrous ethanol

[0223] Preparation method: NMP is first mixed evenly with 50 ml of anhydrous ethanol, 46 g of iohexol is added thereto while stirring, and then the remaining amount of anhydrous ethanol is slowly added and stirred until the solution is clear. Stir for 24 hours to obtain a homogeneous solution, filter it with a 0.22 μm organic filter membrane, and divide it into glass ampoules, seal them, and sterilize them at 121°C for 15 minutes.

[0224] Example 28

[0225] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 25 mg, and the volume fraction of anhydrous ethanol is 95%; the preparation method is the same as that of Example 27.

[0226] composition:

[0227] Iohexol 25g

[0228] NMP 50ml

[0229] 950ml of anhydrous ethanol

[0230] Example 29

[0231] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 40 mg, and the volume fraction of anhydrous ethanol is 90%; the preparation method is the same as that of Example 27.

[0232] composition:

[0233] Iohexol 40g

[0234] NMP 100ml

[0235] 900ml of anhydrous ethanol

[0236] Example 30

[0237] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 70 mg, and the volume fraction of anhydrous ethanol is 85%; the preparation method is the same as that of Example 27.

[0238] composition:

[0239] Iohexol 70g

[0240] NMP 150ml

[0241] 850ml of anhydrous ethanol

[0242] Example 31

[0243] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 140 mg, and the volume fraction of anhydrous ethanol is 80%; the preparation method is the same as that of Example 27.

[0244] composition:

[0245] Iohexol 140g

[0246] NMP 200ml

[0247] 800ml of anhydrous ethanol

[0248] Example 32

[0249] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 230 mg, and the volume fraction of anhydrous ethanol is 75%; the preparation method is the same as that of Example 27.

[0250] composition:

[0251] Iohexol 230g

[0252] NMP 250ml

[0253] 750ml of anhydrous ethanol

[0254] Example 33

[0255] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 345 mg, and the volume fraction of anhydrous ethanol is 70%; the preparation method is the same as that of Example 27.

[0256] composition:

[0257] Iohexol 345g

[0258] NMP 300ml

[0259] 700ml of anhydrous ethanol

[0260] Example 34

[0261] The components and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 57 mg, and the volume fraction of anhydrous ethanol is 80%;

[0262] composition:

[0263] Iohexol 57g

[0264] DMF 200ml

[0265] 800ml of anhydrous ethanol

[0266] Preparation method: DMF is first mixed evenly with 50 ml of anhydrous ethanol, 57 g of iohexol is added thereto while stirring, and then the remaining amount of anhydrous ethanol is slowly added and stirred until the solution is clear. Stir for 24 hours to obtain a homogeneous solution, filter it with a 0.22 μm organic filter membrane, and divide it into glass ampoules, seal them, and sterilize them at 121°C for 15 minutes.

[0267] Example 35

[0268] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 25 mg, and the volume fraction of anhydrous ethanol is 95%; the preparation method is the same as that of Example 34.

[0269] composition:

[0270] Iohexol 25g

[0271] DMF 50ml

[0272] 950ml of anhydrous ethanol

[0273] Example 36

[0274] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 40 mg, and the volume fraction of anhydrous ethanol is 90%; the preparation method is the same as that of Example 34.

[0275] composition:

[0276] Iohexol 40g

[0277] DMF 100ml

[0278] 900ml of anhydrous ethanol

[0279] Example 37

[0280] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 70 mg, and the volume fraction of anhydrous ethanol is 85%: the preparation method is the same as Example 34.

[0281] composition:

[0282] Iohexol 70g

[0283] DMF 150ml

[0284] 850ml of anhydrous ethanol

[0285] Example 38

[0286] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 140 mg, and the volume fraction of anhydrous ethanol is 80%; the preparation method is the same as that of Example 34.

[0287] composition:

[0288] Iohexol 140g

[0289] DMF 200ml

[0290] 800ml of anhydrous ethanol

[0291] Example 39

[0292] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 230 mg, and the volume fraction of anhydrous ethanol is 75%; the preparation method is the same as that of Example 34.

[0293] composition:

[0294] Iohexol 230g

[0295] DMF 250ml

[0296] 750ml of anhydrous ethanol

[0297] Example 40

[0298] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 345 mg, and the volume fraction of anhydrous ethanol is 70%; the preparation method is the same as that of Example 34.

[0299] composition:

[0300] Iohexol 345g

[0301] DMF 300ml

[0302] 700ml of anhydrous ethanol

[0303] Example 41

[0304] The components and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 25 mm2, and the volume fraction of anhydrous ethanol is 95%.

[0305] composition:

[0306] Ioversol 25g

[0307] DMSO 50ml

[0308] 950ml of anhydrous ethanol

[0309] Preparation method: Mix DMSO with 50 ml of anhydrous ethanol at room temperature, add 25 g of iodine ethanol while stirring, and then slowly add the remaining amount of anhydrous ethanol and stir until the solution is clear. Stir for 24 hours to obtain a homogeneous solution, filter it with a 0.22 μm organic filter membrane, divide it into glass ampoules, seal them, and sterilize them at 121°C for 15 minutes.

[0310] Example 42

[0311] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 40 mg, and the volume fraction of anhydrous ethanol is 90%; the preparation method is the same as that of Example 41.

[0312] composition:

[0313] Ioversol 40g

[0314] DMSO 100ml

[0315] 900ml of anhydrous ethanol

[0316] Example 43

[0317] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 70 mg, and the volume fraction of anhydrous ethanol is 85%; the preparation method is the same as that of Example 41.

[0318] composition:

[0319] Ioversol 70g

[0320] DMSO 150ml

[0321] 850ml of anhydrous ethanol

[0322] Example 44

[0323] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 140 mg, and the volume fraction of anhydrous ethanol is 80%; the preparation method is the same as that of Example 41.

[0324] composition:

[0325] Ioversol 140g

[0326] DMSO 200ml

[0327] 800ml of anhydrous ethanol

[0328] Example 45

[0329] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 230 mg, and the volume fraction of anhydrous ethanol is 75%; the preparation method is the same as that of Example 41.

[0330] composition:

[0331] Ioversol 230g

[0332] DMSO 250ml

[0333] 750ml of anhydrous ethanol

[0334] Example 46

[0335] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 345 mg, and the volume fraction of anhydrous ethanol is 70%; the preparation method is the same as that of Example 41.

[0336] composition:

[0337] Ioversol 345g

[0338] DMSO 300ml

[0339] 700ml of anhydrous ethanol

[0340] Example 47

[0341] The components and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 46 mg, and the volume fraction of anhydrous ethanol is 80%;

[0342] composition:

[0343] Ioversol 46g

[0344] NMP 200ml

[0345] 800ml of anhydrous ethanol

[0346] Preparation method: NMP is first mixed evenly with 50 ml of anhydrous ethanol, 46 g of iodine is added thereto while stirring, and then the remaining amount of anhydrous ethanol is slowly added and stirred until the solution is clear. Stir for 24 hours to obtain a homogeneous solution, which is filtered with a 0.22 μm organic filter membrane to obtain a homogeneous solution. The solution is divided into glass ampoules, sealed, and sterilized at 121°C for 15 minutes.

[0347] Example 48

[0348] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 25 mg, and the volume fraction of anhydrous ethanol is 95%; the preparation method is the same as that of Example 47.

[0349] composition:

[0350] Ioversol 25g

[0351] NMP 50ml

[0352] 950ml of anhydrous ethanol

[0353] Example 49

[0354] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 40 mg, and the volume fraction of anhydrous ethanol is 90%; the preparation method is the same as that of Example 47.

[0355] composition:

[0356] Ioversol 40g

[0357] NMP 100ml

[0358] 900ml of anhydrous ethanol

[0359] Example 50

[0360] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 70 mg, and the volume fraction of anhydrous ethanol is 85%; the preparation method is the same as that of Example 47.

[0361] composition:

[0362] Ioversol 70g

[0363] NMP 150ml

[0364] 850ml of anhydrous ethanol

[0365] Example 51

[0366] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 140 mg, and the volume fraction of anhydrous ethanol is 80%; the preparation method is the same as that of Example 47.

[0367] composition:

[0368] Ioversol 140g

[0369] NMP 200ml

[0370] 800ml of anhydrous ethanol

[0371] Example 52

[0372] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 230 mg, and the volume fraction of anhydrous ethanol is 75%; the preparation method is the same as that of Example 47.

[0373] composition:

[0374] Ioversol 230g

[0375] NMP 250ml

[0376] 750ml of anhydrous ethanol

[0377] Example 53

[0378] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 345 mg, and the volume fraction of anhydrous ethanol is 70%; the preparation method is the same as that of Example 47.

[0379] composition:

[0380] Ioversol 345g

[0381] NMP 300ml

[0382] 700ml of anhydrous ethanol

[0383] Example 54

[0384] The components and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 57 mg, and the volume fraction of anhydrous ethanol is 80%;

[0385] composition:

[0386] Ioversol 57g

[0387] DMF 200ml

[0388] 800ml of anhydrous ethanol

[0389] Preparation method: DMF is first mixed evenly with 50 ml of anhydrous ethanol, 57 g of iodine is added thereto while stirring, and then the remaining amount of anhydrous ethanol is slowly added and stirred until the solution is clear. Stir for 24 hours to obtain a homogeneous solution, filter with a 0.22 μm organic filter membrane to obtain a homogeneous solution, divide it into glass ampoules, seal them, and sterilize them at 121°C for 15 minutes.

[0390] Example 55

[0391] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 25 mg, and the volume fraction of anhydrous ethanol is 95%; the preparation method is the same as that of Example 54.

[0392] composition:

[0393] Ioversol 25g

[0394] DMF 50ml

[0395] 950ml of anhydrous ethanol

[0396] Example 56

[0397] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 40 mg, and the volume fraction of anhydrous ethanol is 90%; the preparation method is the same as that of Example 54.

[0398] composition:

[0399] Ioversol 40g

[0400] DMF 100ml

[0401] 900ml of anhydrous ethanol

[0402] Example 57

[0403] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 70 mg, and the volume fraction of anhydrous ethanol is 85%; the preparation method is the same as that of Example 54.

[0404] composition:

[0405] Ioversol 70g

[0406] DMF 150ml

[0407] 850ml of anhydrous ethanol

[0408] Example 58

[0409] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 140 mg, and the volume fraction of anhydrous ethanol is 80%; the preparation method is the same as that of Example 54.

[0410] composition:

[0411] Ioversol 140g

[0412] DMF 200ml

[0413] 800ml of anhydrous ethanol

[0414] Example 59

[0415] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 230 mg, and the volume fraction of anhydrous ethanol is 75%; the preparation method is the same as that of Example 54.

[0416] composition:

[0417] Ioversol 230g

[0418] DMF 250ml

[0419] 750ml of anhydrous ethanol

[0420] Example 60

[0421] The ingredients and contents of each 1000 ml of the hardener composition are as follows, wherein the mass of the contrast agent in each 1 ml of the hardener composition is 345 mg, and the volume fraction of anhydrous ethanol is 70%; the preparation method is the same as that of Example 54.

[0422] composition:

[0423] Ioversol 345g

[0424] DMF 300ml

[0425] 700ml of anhydrous ethanol

[0426] Comparative Example

[0427] Comparative Example 1

[0428] Take 40 ml of anhydrous ethanol at room temperature and add an excess of iopromide while stirring. Seal the container and continue stirring for 6 hours. Pass the solution through a 0.22 μm organic filter membrane to obtain a saturated anhydrous ethanol solution of iopromide.

[0429] Comparative Example 2

[0430] Take 40 ml of anhydrous ethanol at room temperature and add an excess of iohexol while stirring. Seal the container and continue stirring for 6 hours. Pass the filter through a 0.22 μm organic filter membrane to obtain a saturated anhydrous ethanol solution of iohexol.

[0431] Comparative Example 3

[0432] Take 40 ml of anhydrous ethanol at room temperature and add an excess of ioversol while stirring. Seal the container and continue stirring for 6 hours. Pass the solution through a 0.22 μm organic filter membrane to obtain a saturated anhydrous ethanol solution of ioversol.

[0433] Experimental example

[0434] Experimental Example 1

[0435] Content determination: After specificity verification of the saturated anhydrous ethanol solutions of Comparative Examples 1-3, the contents were determined using UV spectrophotometry. The results are shown in the following table:

[0436] Table 1: Saturated solubility of contrast agents in absolute ethanol in Comparative Examples 1-3

[0437] Experimental Example 2

[0438] Composition Status and Clarity Inspection: The hardener compositions prepared in Examples 1-60 were inspected using the light inspection method described in the 2020 edition of the Chinese Pharmacopoeia for Visible Foreign Matter Inspection. The composition status and clarity results are shown in the following table.

[0439] Table 2: State and clarity test results of the compositions of various examples

[0440] Results: All examples were clear and free of foreign matter, demonstrating that they met the requirements for homogeneous solutions. The contrast agent mass fractions in these compositions were all greater than the saturated mass fraction of the contrast agent in anhydrous ethanol, indicating that these cosolvents significantly solubilized these contrast agents in anhydrous ethanol. DMSO was the preferred cosolvent due to its superior solubility.

[0441] Experimental Example 3

[0442] Hemolysis Assay: Prepare a 2% rat erythrocyte suspension. Add 0.3 ml of each of the sclerosant compositions of Examples 6, 7, 14, 26, 27, 34, 46, 47, and 54 and 2.2 ml of normal saline to a colorimetric tube containing 2.5 ml of the 2% rat erythrocyte suspension. Separately, add 2.5 ml of distilled water to a colorimetric tube containing 2.5 ml of the 2% rat erythrocyte suspension as a positive control. Separately, add 2.5 ml of normal saline to a colorimetric tube containing 2.5 ml of the 2% rat erythrocyte suspension as a negative control. Perform the experiment in parallel for both groups.

[0443] Results: The positive control group showed obvious hemolysis, the negative control group showed no hemolysis, and the other groups showed no hemolysis. This indicates that the composition of the present application does not cause hemolysis. See Figure 1. In Figure 1, (a) represents the experimental results of Example 6; (b) represents the experimental results of Example 7; (c) represents the experimental results of Example 14; (d) represents the experimental results of Example 26; (e) represents the experimental results of Example 27; (f) represents the experimental results of Example 34; (g) represents the experimental results of Example 46; (h) represents the experimental results of Example 47; (i) represents the experimental results of Example 54; (j) represents the experimental results of the positive control group; and (k) represents the experimental results of the negative control group.

[0444] Experimental Example 4

[0445] Low-temperature stability test: The hardener compositions prepared in Examples 1-7, 14, 21-27, 34, 41-47, and 54 were stored in a -40°C refrigerator. After 24 hours, the hardener compositions were taken out and the same procedures as in Experimental Example 2 were followed. The results are shown in the following table.

[0446] Table 3: State and clarity test results of the composition of Experimental Example 4 after being placed at -40°C for 24 hours

[0447] Results: After 24 hours at -40 degrees Celsius, no substance was precipitated from the liquid in the ampoules of each group of the above examples, and the state was no different from that of the freshly prepared composition, indicating that the composition of the present application is stable at low temperatures.

[0448] Experimental Example 5

[0449] Imaging experiment 1: Anhydrous ethanol, iopromide anhydrous ethanol saturated solution, and the compositions prepared in Examples 1-7, 13, 14, 20, 27, 33, 34, 40, 47, 53, 54, and 60 were drawn into a 1 ml syringe and placed under X-ray to observe the imaging effect.

[0450] Results: The imaging effects of the compositions prepared in Examples 2, 7, 14, 27, 34, 47, and 54 were compared (the volume percentage of the cosolvent in the compositions prepared in these 7 examples was the same (20%), and the concentration of the contrast agent was similar (±10 mg / ml). The imaging effects of the compositions prepared in Examples 2, 7, 14, 27, 34, 47, and 54 were observed with the naked eye without significant differences, indicating that when the concentration of the contrast agent in the composition was similar (±11 mg / ml), there was no significant difference in the imaging effects of the contrast agent when different cosolvents were used. Compared with the anhydrous ethanol group The X-ray imaging results of the compositions prepared in the iopromide saturated anhydrous ethanol group and Examples 1-6 showed that the contrast (development effect) of the compositions increased with increasing concentration of the contrast agent in the compositions. The development effects of Examples 3-6 were particularly satisfactory, with significantly clearer imaging compared to the anhydrous ethanol group and the iopromide saturated anhydrous ethanol group. Based on the results in Example 2, DMSO was preferred as a cosolvent based on solubility. To minimize the use of cosolvents, a cosolvent volume percentage of 15% was preferred based on the imaging effect. See Figures 2-3.

[0451] 2 shows the experimental results of the anhydrous ethanol group, the iopromide saturated anhydrous ethanol group, Example 1, Example 2, Example 3, Example 4, Example 5, and Example 6 from left to right. FIG3 shows the experimental results of Example 7, Example 14, Example 27, Example 34, Example 47, and Example 54 from left to right.

[0452] Experimental Example 6

[0453] Contrast effect experiment 2: The visualized ethanol hardener composition prepared in Example 4 was encapsulated in polytetrafluoroethylene tubes with inner diameters of 0.3 and 0.6 mm, and the compositions prepared in Examples 7 and 14 were encapsulated in polytetrafluoroethylene tubes with inner diameters of 0.6 mm, and contrast was performed under X-ray.

[0454] Results: The volume fraction of the co-solvent in the compositions prepared in Examples 7 and 14 was 20%, and the contrast agent contents were 46 mg / ml and 57 mg / ml, respectively. The volume fraction of the co-solvent in the composition prepared in Example 4 was 20%, but the contrast agent content therein was 140 mg / ml. Comparing the development effect of the polytetrafluoroethylene tube with an inner diameter of 0.6 mm, it was found that the results were consistent with the results in the experimental example. The development effect was related to the concentration of the contrast agent in the composition. The higher the contrast agent concentration, the more obvious the development effect. Compared with the contrast effects of the 0.3 and 0.6 mm polytetrafluoroethylene tubes perfused with the composition of Example 4, there was a significant difference, and both could clearly image. See Figures 4-5.

[0455] 5 , the inner diameter of the left polytetrafluoroethylene tube is 0.3 mm, and the inner diameter of the right polytetrafluoroethylene tube is 0.6 mm.

[0456] In Figure 6, the inner diameters of the four polytetrafluoroethylene tubes from left to right are 0.6 mm, 0.6 mm, 0.3 mm, and 0.6 mm, respectively. The potting experiments were conducted in Example 7, Example 14, Example 4, and the visualized ethanol hardener composition prepared in Example 4, respectively.

[0457] Experimental Example 7

[0458] Angiography effect experiment 3: The visualized ethanol hardener prepared in Examples 1-6 was encapsulated in a 20 ml vial and compared with the clinically used angiographic contrast agent Uvizan 370. Angiography was performed using the angiography equipment DSA (digital subtraction angiography system).

[0459] Results: Compared with Ultravist 370, the compositions prepared in Examples 3-6 all demonstrated satisfactory imaging effects, enabling clear visualization. The compositions prepared in Examples 1 and 2 failed to demonstrate clear imaging due to the low iodine content of the contrast agent. Clinically, anhydrous ethanol injection is used by mixing anhydrous ethanol with Ultravist 370 in a 1:1 volume ratio to achieve visualization. Pure Ultravist 370 was used for comparison. The clinical concentration is 0.5 times that of pure Ultravist 370, resulting in lower contrast, but still meeting imaging requirements. See Figure 6.

[0460] In FIG6 , from left to right, the vials are filled with Example 1, Example 2, Example 3, Example 4, Example 5, Example 6, and Uvixin 370.

[0461] Experimental Example 8

[0462] Stability test: The hardened samples prepared in Examples 4, 7, 14, 24, 27, 34, 44, 47, and 54 were subjected to an accelerated stability test. The samples were placed at a temperature of 40°C ± 2°C and a humidity of 75% ± 5% for 6 months. Samples were taken before sterilization, and 1, 2, 3, and 6 months after sterilization to detect ethanol content.

[0463] Table 4: Ethanol content of the preferred embodiment composition accelerated test

[0464] As can be seen from the stability data in Table 4 above, the drug content of the hardener composition of the present invention is within the specified range in the accelerated stability test, and the hardener composition has good stability.

[0465] Experimental Example 9

[0466] Rat venous sclerosis and embolism experiment: SD rats were anesthetized, the thigh hair was shaved, and the dorsalis foot vein was injected proximally with anhydrous ethanol and the sclerosants prepared in Examples 6, 7, and 14. The sclerosis and embolism were examined by transillumination.

[0467] Results: High-intensity light was applied to the thighs of healthy rats. Observation of the other side revealed no vascular striae in the uninjected rat legs (Figure 7). Following injection of 0.1 ml of anhydrous ethanol and observation under the same high-intensity light, the vascular striae were clearly visible, appearing dark blue, indicating effective sclerosis and embolization of the vessels. No redness, swelling, or inflammation of the surrounding tissues occurred (Figure 8). The rats remained normal after injection. Injection of 0.1 ml of the sclerosant compositions prepared in Examples 6, 7, and 14 resulted in sclerosis and embolization of the target vessels, similar to those following anhydrous ethanol injection. The length of the embolization was longer than that following the same dose of anhydrous ethanol injection. No redness, swelling, or inflammation of the surrounding tissues occurred (Figures 9-11). The rats remained normal after injection. The longer embolization of the vessels with the compositions prepared in the examples at the same dose was likely due to the increased viscosity of the solution, which, compared to the anhydrous ethanol composition, allowed the compositions to remain in the vessels longer, resulting in a more effective sclerosis and embolization. Based on the above results, the composition is highly safe, and the introduction of the cosolvent does not weaken the sclerotic embolic ability of anhydrous ethanol, and may enhance the sclerotic effect on blood vessels due to the increase in viscosity.

[0468] The present invention has been described in detail above. Specific examples are used herein to illustrate the principles and implementation methods of the present invention. The description of the above embodiments is only intended to help understand the method and core concept of the present invention. It should be noted that those skilled in the art may make several improvements and modifications to the present invention without departing from the principles of the present invention, and such improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. A visualization ethanol hardener composition comprising anhydrous ethanol, a contrast agent and a cosolvent.

2. The composition according to claim 1, wherein the total volume fraction of the anhydrous ethanol and the cosolvent is 1, and the contrast agent is dissolved therein to form a homogeneous solution.

3. The composition according to claim 1 or 2, wherein the contrast agent is selected from one or more of iopromide, iohexol and ioversol, and the cosolvent is water-free and miscible with ethanol, and is selected from one or more of DMSO, NMP and DMF.

4. The composition according to any one of claims 1 to 3, wherein the volume fraction of the anhydrous ethanol is 70-95%, and the volume fraction of the co-solvent is 5-30%.

5. The composition according to any one of claims 1 to 4, wherein the mass-to-volume ratio of the contrast agent to the composition is 10 mg / ml-344 mg / ml.

6. The composition according to any one of claims 1 to 4, wherein the mass volume ratio of iodine element in the contrast agent to the composition is 5 mg / ml-165 mg / ml, preferably 67 mg / ml.

7. A method for preparing the visual ethanol hardener composition according to any one of claims 1 to 6, comprising: Mixing anhydrous ethanol and a cosolvent in a volume ratio of 70-95% by volume of anhydrous ethanol and 5-30% by volume of the cosolvent; Add contrast agent and stir to disperse and fully dissolve the contrast agent; The fully dissolved mixed solution is filtered to obtain a homogeneous liquid; or a centrifugal method is used to obtain a homogeneous liquid by taking a supernatant after high-speed centrifugation; or the fully dissolved mixed solution is allowed to stand and the supernatant is taken to obtain a homogeneous liquid.

8. The preparation method according to claim 7, further comprising: The homogeneous liquid is placed in an ampoule, sealed, and sterilized at high temperature. The temperature of the high temperature sterilization is preferably 115° C.-121° C., and the sterilization time is preferably 7-30 minutes.

9. Use of the composition according to any one of claims 1 to 6 or the visualized anhydrous ethanol hardener composition prepared according to the preparation method according to any one of claims 7 to 8 in the preparation of sclerotherapy drugs.

10. A method for treating hemangioma or vascular malformation, comprising using the composition according to any one of claims 1 to 6 or the visualized anhydrous ethanol sclerosant composition prepared according to the preparation method according to any one of claims 7 to 8.

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