Iodine contrast agent composition
A homogeneous iodine contrast agent-ethanol composition addresses the complexity and risks of traditional sclerotherapy by offering precise, single-step vascular embolization with reduced tissue damage and improved safety.
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- CHENGDU BEITE SOUP IND CO LTD
- Filing Date
- 2024-06-18
- Publication Date
- 2026-06-30
AI Technical Summary
Current sclerotherapy techniques using iopromide and anhydrous ethanol are complex, time-consuming, and pose risks due to ethanol leakage, while conventional suspensions increase clinical risks.
A homogeneous iodine contrast agent-ethanol composition with specific concentrations of iopromide, ethanol, and water for injection, prepared by dissolving iopromide in water and adding anhydrous ethanol, providing a single-step injectable solution for sclerotherapy.
The composition achieves precise vascular embolization with fewer side effects, lower tissue damage, and improved therapeutic accuracy, reducing the complexity and risks associated with traditional methods.
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Abstract
Description
Technical Field
[0001] The present invention relates to the field of pharmaceutical technology, specifically to an iodine contrast agent ethanol composition, its manufacturing method, and its use.
Background Art
[0002] Venous malformation is a commonly seen congenital venous developmental disorder. The incidence rate is 0.01% - 0.02%, without obvious gender difference, and it may affect every part of the body. The most common sites include the oral cavity, airway, and head and neck. Severe venous malformation affects multiple tissues and organs and may cause various complications leading to physical disabilities and death. For example, venous malformation in the head and neck can cause obvious appearance deformities, functional disorders such as chewing disorders and respiratory obstruction. Venous malformation affecting the limbs and joints often causes severe swelling, pain, joint stiffness, limb functional disorders, and even physical disabilities in severe cases. Some patients may also be endangered by life due to local intravascular coagulation disorder (LIC) or disseminated intravascular coagulation disorder (DIC). The international mainstream treatment for venous malformation is endovascular sclerosis treatment. Its main principle is to damage and destroy vascular endothelial cells by various mechanisms, causing occlusion and fibrosis of the blood cavities in the lesion. However, all existing various sclerosing agents have obvious advantages and disadvantages, and it is difficult to meet the requirements of diverse and complex venous malformation treatments.
[0003] Arteriovenous malformations (AVMs) are rare congenital high-flow vascular malformations in which arteries and veins are abnormally connected. The main manifestation is the direct connection of the abnormally connected arteries and veins in the absence of a normal capillary bed, forming numerous microarteriovenous fistulas. AVMs commonly occur in the neck, face, and extremities. Clinical manifestations include redness, swelling, fever, and pulsatile tumors. Most AVMs exhibit progressive development, potentially leading to serious bleeding, infection, ulceration, necrosis, functional impairment, and even heart failure. Endovascular embolization plays a crucial role in AVM treatment, providing favorable outcomes for AVMs that were previously considered inoperable or carried extremely high surgical risks.
[0004] Abdominal cystic diseases often affect organs such as the liver, kidneys, ovaries, and pelvic lymph nodes, with liver, kidney, and ovarian cysts being the most common. Their development is associated with a series of congenital and acquired cystic lesions, and many patients have no obvious clinical symptoms and usually do not require treatment. However, as the cyst grows, it can cause symptoms such as abdominal pain and lower back pain, and may cause pressure and migration on nearby tissues, so timely treatment measures are necessary. Traditionally, treatment has been performed using single puncture and drainage, but the recurrence rate of cysts is high, and furthermore, traditional surgery carries significant risks, severely impacting the patient's prognosis. With the development of imaging techniques such as computed tomography (CT) and ultrasound, image-guided percutaneous sclerotherapy is gradually replacing surgery. It has advantages such as being less invasive, less painful, repeatable, simpler to operate, having good therapeutic effects, and a lower recurrence rate than simple cystic drainage treatment. The principle of sclerotherapy is that a sclerosing agent, such as anhydrous ethanol, comes into contact with the cyst wall, causing the proteins in the cyst wall cells to coagulate and denature, destroying the cells, hardening and closing the cyst wall, stopping the secretion of cyst fluid, and thereby achieving the therapeutic goal of shrinking or eliminating the cyst to the greatest extent possible.
[0005] Stubborn pain refers to persistent pain that is difficult to control with some or all therapeutic measures. Depending on the etiology, it can be classified as cancer pain or non-cancer pain, and it may reside in the central nervous system or the periphery (including any part of the body and internal organs). Depending on the nature of the pain, it can be classified as nociceptive pain or neuropathic pain. For some patients with stubborn pain, various methods have been tried but the treatment is ineffective. In such cases, nerve destructive therapy can be selected after strictly controlling the indications and obtaining the patient's informed consent. Nerve destructive therapy refers to the goal of treating stubborn pain by destroying the function of ganglia, nerve dries, nerve plexuses, or intrashear nerves using methods such as chemicals, radiofrequency thermocoagulation, or surgery. The most commonly used drugs for nerve destructive therapy under intervention guidance are ethanol (50%~100%) and phenol (5%~10%).
[0006] Anhydrous ethanol is a commonly used liquid embolizer that rapidly destroys vascular endothelial cells, denatures hemoglobin, causes widespread thrombus formation and fibrosis within blood vessels, can promote embolization of drainage veins and thrombus formation within lesions, rapidly dehydrates and necrotizes cells, closes cysts, and destroys nerves. It is currently widely used in clinical practice for interventional treatment of cysts, arteriovenous malformations, and venous malformations in living organisms, as well as in nerve destruction therapy.
[0007] Iopromide is a non-ionic, hypoosmolar contrast agent primarily used in computed tomography (CT), digital subtraction angiography (DSA) using arterial / venous approaches, and endoscopic retrograde cholangiopancreatography (ERCP).
[0008] Anhydrous ethanol and iopromide injection can be used in combination for sclerotherapy guided by CT or digital subtraction angiography (DSA). Conventional CT or DSA-guided sclerotherapy techniques are performed in two steps: first, a contrast agent (iopromide injection) is injected after puncture to fill the lesion and clearly define the location and size of the lesion; and then, a non-developable sclerosing agent (anhydrous ethanol) is injected into the lesion cavity in place of the original contrast agent. This technique is relatively complicated, time-consuming, and the ethanol does not develop under CT or DSA, potentially leaking out of the lesion during the treatment process, increasing the risk of side effects.
[0009] Conventional techniques involved mixing iopromide and anhydrous ethanol, then adding a suspension aid to produce an iopromide-anhydrous ethanol suspension. While this improved the complexity of the sclerotherapy procedure described above, this formulation is a suspension, posing significant risks for clinical use. [Overview of the project]
[0010] In one or more embodiments of the present invention, a drug composition is provided that contains an iodine contrast agent, ethanol, and water, wherein, depending on the volume of the drug composition, the content of the iodine contrast agent is 208 mg / mL to 624 mg / mL, and the content of the ethanol is 484 mg / mL to 677 mg / mL.
[0011] In one or more embodiments, the content of the iodine contrast agent in the drug composition is 220 mg / mL, 250 mg / mL, 280 mg / mL, 300 mg / mL, 350 mg / mL, 400 mg / mL, 450 mg / mL, 500 mg / mL, 550 mg / mL, or 600 mg / mL, depending on the volume of the drug composition.
[0012] In one or more embodiments, the ethanol content of the drug composition is 500 mg / mL, 550 mg / mL, 600 mg / mL, or 650 mg / mL, depending on the volume.
[0013] In one or more embodiments, the iodine contrast agent is selected from iopromide, iobitridol, iopamidol, iomeprol, iodixanol, ioversol, iohexol, and iotrolan.
[0014] In one or more embodiments, the iodine contrast agent is iopromide or iobitridol.
[0015] In one or more embodiments, the drug composition comprises an iodine contrast agent, ethanol, and water.
[0016] In one or more embodiments, the content of the iodine contrast agent is 229 mg / mL to 280 mg / mL, depending on the volume of the drug composition.
[0017] In one or more embodiments, the ethanol content of the drug composition is 630 mg / mL to 677 mg / mL, depending on the volume.
[0018] In one or more embodiments, the ethanol content of the drug composition is 630 mg / mL to 658 mg / mL, depending on the volume.
[0019] In one or more embodiments, the water is water for injection.
[0020] In one or more embodiments, the water content of the drug composition is at least 29 mg / mL, depending on the volume.
[0021] In one or more embodiments, the water content of the drug composition is 30 mg / mL to 125 mg / mL, depending on the volume.
[0022] In one or more embodiments, depending on the volume of the drug composition, the water content is 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, or 120 mg / mL.
[0023] In one or more embodiments, depending on the volume of the drug composition, the water content is 33 mg / mL to 115 mg / mL.
[0024] In one or more embodiments, depending on the volume of the drug composition, the water content is 70 mg / mL to 115 mg / mL.
[0025] In one or more embodiments, depending on the volume of the drug composition, the iodine content is 100 mg / mL to 300 mg / mL.
[0026] In one or more embodiments, depending on the volume of the drug composition, the iodine content is 150 mg / mL, 200 mg / mL, or 250 mg / mL.
[0027] In one or more embodiments, depending on the volume of the drug composition, the iodine content is 110 mg / mL to 270 mg / mL.
[0028] In one or more embodiments, depending on the volume of the drug composition, the iodine content is 110 mg / mL to 134 mg / mL.
[0029] In one or more embodiments, depending on the volume of the drug composition, the iodinated contrast agent is iopromide, and the content of iopromide is 208 mg / mL to 624 mg / mL (for example, 250 mg / mL, 300 mg / mL, 350 mg / mL, 400 mg / mL, 450 mg / mL, 500 mg / mL, 550 mg / mL, or 600 mg / mL), and the content of ethanol is 484 mg / mL to 677 mg / mL (for example, 500 mg / mL, 550 mg / mL, 600 mg / mL, or 650 mg / mL).
[0030] In one or more embodiments, due to the volume of the drug composition, the iodine contrast agent is iopromide, the content of the iopromide is 208 mg / mL to 624 mg / mL (for example, 220 mg / mL, 250 mg / mL, 280 mg / mL, 300 mg / mL, 350 mg / mL, 400 mg / mL, 450 mg / mL, 500 mg / mL, 550 mg / mL, or 600 mg / mL), the content of the ethanol is 484 mg / mL to 677 mg / mL (for example, 500 mg / mL, 550 mg / mL, 600 mg / mL, or 650 mg / mL), and the content of the water (for example, water for injection) is at least 29 mg / mL (for example, 30 mg / mL to 125 mg / mL, specifically, for example, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, or 120 mg / mL).
[0031] In one or more embodiments, the iodine contrast agent in the drug composition is completely dissolved, and the drug composition is a homogeneous solution.
[0032] In one or more embodiments, the drug composition is prepared as an injection solution.
[0033] In one or more embodiments of the present invention, an injectable preparation containing the drug composition according to the present invention is provided.
[0034] In one or more embodiments of the present invention, a method for manufacturing the drug composition according to the present invention, which includes adding an iodine contrast agent to water for injection at the above-described content, stirring while heating until completely dissolved, cooling to 50°C or lower, adding anhydrous ethanol and stirring uniformly, and obtaining the drug composition after filtration, is provided.
[0035] In one or more embodiments of the present invention, a method for manufacturing the injectable preparation according to the present invention, which includes tank filling and sterilizing the drug composition according to the present invention to obtain the injectable preparation, is provided.
[0036] In one or more embodiments, the iodine contrast agent is selected from iopromide, iovitridol, iopamidol, iomeprole, iodixanol, ioversol, iohexol, and iotrolane.
[0037] In one or more embodiments, the iodine contrast agent is iopromide or iobitridol.
[0038] In one or more embodiments of the present invention, the use of a drug composition or injectable formulation according to the present invention in the manufacture of a drug for treating vascular malformations, abdominal cystic diseases, or persistent pain is provided.
[0039] In one or more embodiments, the vascular malformation is a venous malformation, arteriovenous malformation, lymphatic malformation, or mixed malformation.
[0040] In one or more embodiments, the abdominal cystic disease is a liver cyst, a kidney cyst, an ovarian cyst, or a pelvic lymphoid cyst.
[0041] In one or more embodiments, the drug for treating persistent pain is a drug for nerve destruction.
[0042] In one or more embodiments of the present invention, a drug composition or injectable formulation according to the present invention, which is used as a drug, is provided.
[0043] In one or more embodiments of the present invention, a drug composition or injectable formulation according to the present invention is provided for the treatment of vascular malformations, abdominal cystic diseases, or persistent pain.
[0044] In one or more embodiments of the present invention, a method is provided for treating vascular malformations, abdominal cystic diseases, or persistent pain, the method comprising administering a drug composition or injectable formulation according to the present invention to a subject in need thereof.
[0045] In one or more embodiments, the vascular malformation is a venous malformation, arteriovenous malformation, lymphatic malformation, or mixed malformation.
[0046] In one or more embodiments, the abdominal cystic disease is a liver cyst, a kidney cyst, an ovarian cyst, or a pelvic lymphoid cyst.
[0047] In one or more embodiments, the drug for treating persistent pain is a drug for nerve destruction.
[0048] In one or more embodiments, the drug composition is characterized in that the iodine contrast agent is iopromide, the iopromide content is 229 mg / mL to 280 mg / mL, the ethanol content is 630 mg / mL to 677 mg / mL, and the water for injection content is 33 mg / mL to 115 mg / mL.
[0049] In one or more embodiments, the drug composition contains iopromide as the iodine contrast agent, with an iopromide content of 229 mg / mL, an ethanol content of 630 mg / mL to 658 mg / mL, and a water for injection content of 70 mg / mL to 115 mg / mL.
[0050] The present invention provides an iodine contrast agent-ethanol drug composition containing an iodine contrast agent, ethanol, and water for injection, wherein the ethanol content is 484 mg / mL to 677 mg / mL, the iodine contrast agent content is 208 mg / mL or more, and the water for injection content is greater than 29 mg / mL. Furthermore, the composition is a homogeneous solution, and the iodine contrast agent is completely dissolved within the composition. Furthermore, a drug composition is provided in which the iodine contrast agent is selected from iopromide, iobitridol, iopamidol, iomeprole, iodixanol, ioversol, iohexol, and iotrolane, and is preferably iopromide or iobitridol.
[0051] The present invention further provides a drug composition comprising an iodine contrast agent, ethanol, and water for injection, wherein the ethanol content is 484 mg / mL to 677 mg / mL, the iodine contrast agent content is 208 mg / mL or more, and the water for injection content is greater than 29 mg / mL, the composition is a homogeneous solution, the iodine contrast agent is completely dissolved in the composition, and furthermore, the iodine contrast agent is selected from iopromide, iovitridol, iopamidol, iomeprole, iodixanol, ioversol, iohexol, iotorolane, and etiodized poppyseed oil, preferably iopromide or iovitridol.
[0052] Furthermore, in the iodine contrast agent-ethanol drug composition provided in the present invention, the content of the iodine contrast agent is preferably 208 mg / mL to 624 mg / mL, more preferably 229 mg / mL to 280 mg / mL.
[0053] Furthermore, in the iodine contrast agent-ethanol drug composition provided in the present invention, the iodine content in the composition is preferably 100 mg / mL to 300 mg / mL, more preferably 110 mg / mL to 270 mg / mL, and the iodine content in some specific compositions according to the present invention is preferably 110 mg / mL to 134 mg / mL.
[0054] Furthermore, in the iodine contrast agent-ethanol drug composition provided in the present invention, the ethanol content is preferably 630 mg / mL to 677 mg / mL, more preferably 630 mg / mL to 658 mg / mL.
[0055] Furthermore, in the iodine contrast agent-ethanol drug composition provided in the present invention, the content of water for injection is preferably 30 mg / mL to 125 mg / mL, more preferably 33 mg / mL to 115 mg / mL, and the proportion of water for injection in some specific compositions according to the present invention is preferably 70 mg / mL to 115 mg / mL.
[0056] Furthermore, in the iodine contrast agent-ethanol drug composition provided in the present invention, the iodine contrast agent is preferably iobromide in an amount of 229 mg / mL to 280 mg / mL, the ethanol is preferably in an amount of 630 mg / mL to 677 mg / mL, and the water for injection is preferably in an amount of 33 mg / mL to 115 mg / mL.
[0057] Furthermore, in the iodine contrast agent-ethanol drug composition provided in the present invention, the iodine contrast agent is preferably iopromide in an amount of 229 mg / mL, the ethanol content is preferably 630 mg / mL to 658 mg / mL, and the water for injection content is preferably 70 mg / mL to 115 mg / mL.
[0058] The present invention further provides a method for producing a drug composition of iodine contrast agent-ethanol, characterized in that, in the above-mentioned formulation ratio, the iodine contrast agent raw material is added to water for injection, heated until completely dissolved, the solution is cooled to 50°C or below, anhydrous ethanol is added and uniformly stirred, filtered, filled into a tank, and sterilized.
[0059] In another embodiment, the present invention provides the use of the above-described drug composition in the treatment of vascular malformations, wherein the vascular malformations are venous malformations, arteriovenous malformations, lymphatic malformations, and mixed malformations.
[0060] Furthermore, the aforementioned uses include those of drugs used for nerve destructive treatment of venous malformations, arteriovenous malformations, abdominal cystic diseases, hepatic cysts, renal cysts, ovarian cysts, pelvic lymphoid cysts, and stubborn pain.
[0061] In one or more embodiments, the drug composition according to the present invention is in a solution state and is a clear solution with a uniform and stable appearance.
[0062] In one or more embodiments, the drug composition according to the present invention exhibits good solution stability and does not show solid precipitation even when subjected to vigorous vibration or left standing under open conditions.
[0063] In one or more embodiments, the drug composition according to the present invention exhibits good in-vitro and in-vitro development effects, and good development effects were achieved with a low content of iodine contrast agent (e.g., iopromide).
[0064] In one or more embodiments, the drug composition according to the present invention satisfies the requirement of vascular embolization in clinical therapeutic effects and achieves the objective of visible embolization therapy. In one or more embodiments, the drug composition according to the present invention achieves an in-vitro development effect, making blood vessels clearly visible to the naked eye, and the vascular embolization effect satisfies the clinical therapeutic effect.
[0065] In one or more embodiments, the drug composition according to the present invention has few side effects. In one or more embodiments, the drug composition according to the present invention causes less damage to surrounding tissue than anhydrous ethanol.
[0066] In one or more embodiments, the drug composition according to the present invention has a good vascular embolization effect, a good intracellular and extracellular DSA development effect, improves the accuracy of vascular embolization therapy, and achieves a better therapeutic effect.
[0067] In one or more embodiments, the drug composition according to the present invention enhances the accuracy of vascular embolization therapy while causing significantly less damage to surrounding tissue than anhydrous ethanol, and in addition, there is no apparent increase in the degree of proliferation and / or necrosis of surrounding tissue. In one or more embodiments, the drug compositions according to the present invention further enhance therapeutic effects, reduce contrast agent content, lower usage costs, and reduce potential clinical risks, while ensuring low irritancy and fewer adverse reactions.
[0068] In one or more embodiments, the drug compositions according to the present invention (e.g., iobromide-ethanol drug compositions, iovitridol-ethanol drug compositions) can be dynamically monitored during the treatment process, development and treatment can be completed with a single injection procedure, improving the cumbersome problem of performing traditional DSA-guided techniques and sclerotherapy separately, resulting in precise treatment, clear therapeutic effects, and a low rate of adverse reactions.
[0069] In one or more embodiments, compared to conventional DSA-guided sclerotherapy techniques, the drug compositions according to the present invention reduce the cumbersome procedure of injection in two steps for treatment and contrast imaging, allowing treatment and development to be completed with a single injection step, and achieving the objective of dynamic monitoring during the treatment process.
[0070] In one or more embodiments, the drug composition according to the present invention has higher therapeutic accuracy, fewer side effects, less irritation, and greater safety and stability.
[0071] In one or more embodiments, the drug composition according to the present invention has a much lower iodine contrast agent content than commercially available mainstream iopromide injection solutions, and can achieve a good development effect with a low content of iodine contrast agent, resulting in lower usage costs and lower clinical risks.
[0072] In one or more embodiments, the drug composition according to the present invention has one or more of the following favorable technical effects: good vascular embolization effect; good in vitro and extracellular DSA development effect; can meet the clinical demand for image "visualization"; the solution is clear and homogeneous and has good stability; it is safe, has low irritancy, has little effect on surrounding tissue, and does not cause, for example, tissue proliferation and / or necrosis. [Brief explanation of the drawing]
[0073] [Figure 1] Examples 5-7 and the in vitro development effect of the commercially available formulation Ultravist300 are shown. [Figure 2]Example 1 shows the in vivo development effect of the commercially available formulation Ultravist 300 and physiological saline. [Figure 3] Experimental Example 3 shows the in-vivo development effect of Example 1 and Comparative Example C. Detailed description of the invention
[0074] The following embodiments are illustrative examples of the present invention, and the scope of protection of the present invention is not limited to these embodiments.
[0075] Manufacturing Example 1 Table 1 shows the formulation composition of the iodine contrast agent-ethanol injection solution.
[0076] [Table 1]
[0077] The manufacturing method was as follows: Water for injection was added to the preparation tank in the prescribed amount, iopromide was slowly added in the prescribed amount, and the mixture was heated and stirred until completely dissolved. The solution was then cooled to below 50°C, anhydrous ethanol was added in the prescribed amount, and the mixture was stirred uniformly. After filtration, filling into a tank, and sterilization, iopromide-ethanol injection solution was obtained.
[0078] Manufacturing Example 2 Referencing the manufacturing method of Example 1, the iodine contrast agent-ethanol injection solutions of Examples 2 to 9 were prepared according to the formulations in Table 2 below.
[0079] [Table 2]
[0080] The iodine contrast agent-ethanol injection solutions obtained in Examples 1-9 were all homogeneous and clear solutions. After taking 10 mL of each sample, vigorously shaking it for 30 minutes, and then allowing it to stand, each sample solution remained homogeneous and clear. Experiments revealed that a drug composition containing iodine contrast agent, ethanol, and water for injection (for example, with an ethanol content of 484 mg / mL to 677 mg / mL and an iodine contrast agent content of 208 mg / mL to 624 mg / mL) can yield a homogeneous, stable, and clear solution composition.
[0081] Comparative examples A~D Referencing the manufacturing method of Example 1, an iodine contrast agent-ethanol injection solution was prepared according to the formulation composition shown in Table 3.
[0082] [Table 3]
[0083] Comparative Examples A to D all yielded homogeneous and clear solutions. After taking 10 mL of each sample, vigorously shaking it for 30 minutes, and then allowing it to stand, each sample solution remained homogeneous and clear.
[0084] Comparative Example E Iodine contrast agent-ethanol injection solution was prepared according to the formulation composition shown in Table 4.
[0085] [Table 4]
[0086] The manufacturing method was the same as in Example 1. After adding 68.22 g of anhydrous ethanol to the final volume, the solution became slightly cloudy. A 10 mL sample was taken, vigorously shaken for 30 minutes, and then allowed to stand, after which the cloudiness of the sample became more pronounced. As can be seen from this, a uniform and clear iodine contrast agent-ethanol solution was not obtained in Comparative Example E.
[0087] Comparative example F 20 g of iobromide powder was dispersed in 50 mL (39.47 g) of anhydrous ethanol, and after shaking, an iobromide-anhydrous ethanol suspension was obtained. Then, 0.05 g of Tween 80 was added to the suspension, and after shaking to uniformly disperse it, anhydrous ethanol was added to a final volume of 100 mL to obtain a mixed suspension injection of iobromide-anhydrous ethanol.
[0088] Comparative Example G 25 mL of commercially available iopromide injection solution (containing 0.769 g / mL of iopromide) was evaporated by rotation to remove the solvent, and a powder was obtained. 25 mL (19.73 g) of anhydrous ethanol was then added, and the mixture was pre-dispersed by sonication for 20 minutes. The pre-dispersed mixture was then placed in a reaction vessel, pressurized to 15 MPa using supercritical carbon dioxide, maintained at 40°C and 1000 rpm / min for 2 hours, and finally reduced to atmospheric pressure to obtain an iopromide-anhydrous ethanol solution. A 10 mL sample was taken, vigorously shaken for 30 minutes, and then allowed to stand; the sample solution showed slight turbidity.
[0089] Experimental Example 1a Using an INFX-9000C digital subtraction angiography (DSA) system (manufacturer: Canon), in vitro development was performed using the solutions from Examples 5-7 and commercially available iobromide injection solution (Ultravist300), and the development results are shown in Figure 1.
[0090] As is clear from the development results, the iobromide-ethanol injection solutions obtained in Examples 5-7 showed no significant difference in in vitro development depth under DSA compared to the commercially available formulation (Ultravist300). The applicant found through experiments that the drug compositions provided in the present invention, which contain iodine contrast agent, ethanol, and water for injection (for example, ethanol content of 484 mg / mL to 677 mg / mL, iodine contrast agent content of 208 mg / mL to 624 mg / mL), have good in vitro development effects, and that good development effects were achieved with low concentrations of iobromide.
[0091] Experimental Example 1b Two mL each of physiological saline, commercially available iobromide injection (Ultravist300), and iodine contrast agent-ethanol injection from Example 1 were injected into the bilateral renal arteries of New Zealand rabbits. All injections were completed within 10 seconds, and in vivo development was performed under DSA. The development results are shown in Figure 2.
[0092] As is clear from the development results, the blood vessels of the kidney were clearly visible under DSA, and the iobromide-ethanol injection solution obtained in Example 1 was able to produce animal organ images that were distinguishable to the naked eye. Through experiments, the applicant found that the drug composition according to the present invention, which contains an iodine contrast agent, ethanol, and water for injection (for example, with an ethanol content of 484 mg / mL to 677 mg / mL and an iodine contrast agent content of 208 mg / mL to 624 mg / mL), has a good in vivo development effect and can meet the clinical demand for image "visualization".
[0093] Experimental Example 2 Eighteen New Zealand rabbits were divided into three groups of six. Each group received a slow injection into the vein at the right ear margin of each rabbit. Each group received 1 mL of physiological saline, 1 mL of anhydrous ethanol, and 1 mL of iobromide-ethanol injection solution according to Example 1. After injection, the needle was withdrawn and the injection site was marked. The rabbits were observed for 14 days after administration, and ear tissue was collected and pathologically stained. The degree of vascular embolism was evaluated by level: Level "0" if no embolism was observed; Level "I" if partial embolism was observed; Level "II" if complete embolism was observed. Simultaneously, the degree of surrounding tissue damage was evaluated and categorized as follows: Level "0" if no lesions were found in the perivascular tissue; Level "I" if there were no or slight increases in perivascular inflammatory cells, mild proliferation of granulation tissue, and no obvious tissue thickening; Level "II" if there was a slight increase in perivascular inflammatory cells, obvious proliferation of granulation tissue, and tissue thickening; Level "III" if there was partial necrosis of the perivascular tissue, and the necrotic area was less than 1 / 3 of the sampled tissue cross-section; Level "IV" if there was extensive necrosis of the perivascular tissue, and the necrotic area accounted for more than 1 / 3 of the sampled tissue.
[0094] Table 5 shows the experimental results regarding vascular embolism and surrounding tissue damage in the three groups.
[0095] [Table 5]
[0096] In the table, N represents the number of animals in each group. The chi-squared test was used for difference analysis between groups. " / " indicates that the test was not applicable or that this group did not show a statistically significant difference compared to the other groups. p<0.05 indicates a statistically significant difference.
[0097] As is clear from the results of the exemplary experiments described above, the iopromide-ethanol injection solution according to Example 1 showed no significant difference in vascular embolization effect compared to anhydrous ethanol, and was slightly superior to the embolization effect of anhydrous ethanol in terms of the incidence of complete embolization. Therefore, it can be stated that the iopromide-ethanol injection solution according to the present invention has a good vascular embolization effect and can meet the clinical treatment needs for venous malformations. Example 1 showed significantly lower surrounding tissue damage than anhydrous ethanol and had lower side effects and higher therapeutic accuracy compared to anhydrous ethanol.
[0098] Experimental Example 3 Forty New Zealand rabbits were divided into 10 groups, with four rabbits per group. Iopromide-ethanol injection solutions were slowly injected into the vein of the right ear margin of each rabbit in each group. Each group received 1 mL of iopromide-ethanol injection solution according to Example 1, Example 3, Example 4, Example 6, Comparative Example A, Comparative Example B, Comparative Example C, Comparative Example D, and Comparative Example F. After injection, the needle was withdrawn and the injection site was marked. Intravascular development was performed on each group of animals under DSA, and the DSA development intensity value was recorded. The animals were then observed for 14 days, and ear tissue was collected and pathologically stained. Each animal was scored according to the degree of vascular embolism: 0 points if no embolism was observed; 1 point if partial embolism was observed; and 2 points if complete embolism was observed. Simultaneously, each animal was scored according to the degree of surrounding tissue damage: 0 points if no lesions were observed in the perivascular tissue; 1 point if there were no or slight increases in perivascular inflammatory cells, mild proliferation of granulation tissue, and no obvious tissue thickening; 2 points if there was a slight increase in perivascular inflammatory cells, obvious proliferation of granulation tissue, and tissue thickening; 3 points if there was partial necrosis of the perivascular tissue, and the necrotic area was less than 1 / 3 of the collected tissue cross-section; 4 points if there was extensive necrosis of the perivascular tissue, and the necrotic area accounted for 1 / 3 or more of the collected tissue. The average scores for the degree of vascular embolism and the degree of surrounding tissue damage for each group of animals were used as the venous occlusion pathology score and the surrounding tissue damage pathology score. Figure 3 shows the development effect of iopromide-ethanol injection solution in Example 1 and Comparative Example C. The experimental results for each group are shown in Table 6.
[0099] [Table 6]
[0100] " / " indicates that measurement is not performed.
[0101] As is clear from the results of the exemplary experiments described above, comparative examples A and B had venous occlusion pathology scores of less than 0.5, indicating poor venous occlusion; comparative examples C, D, and F had surrounding tissue damage pathology scores of 1.5 or higher, indicating clear surrounding tissue necrosis and clear side effects; and comparative examples C, D, and F had weak DSA development intensity, making it difficult to visually assess the vascular condition.
[0102] Based on the above experiments, it can be stated that the present invention exhibits good in-vitro and in-vitro DSA development effects, allows for visual identification of internal blood vessels, has a stronger vascular embolization effect, meets the clinical requirements for precision therapy, has fewer side effects, causes significantly less damage to surrounding tissues than anhydrous ethanol, and did not show a clear increase in the degree of proliferative necrosis.
[0103] Experimental Example 4 The samples obtained in Example 1, Example 3, Example 4, and Comparative Example G were left open under room temperature conditions to examine the stability of each sample solution. The results are shown in Table 7.
[0104] [Table 7]
[0105] As is clear from the results of the exemplary experiments described above, Comparative Example G had a clear stability problem when left standing under open conditions. The iopromide-ethanol injection solution according to the present invention had better standing stability than Comparative Example G. The experiments described above demonstrate that the drug composition according to the present invention, which contains an iodine contrast agent, ethanol, and water for injection (for example, with an ethanol content of 484 mg / mL to 677 mg / mL and an iodine contrast agent content of 208 mg / mL to 624 mg / mL), is less prone to solid precipitation and has good solution stability even when left standing under open conditions.
Claims
1. A drug composition containing an iodine contrast agent, ethanol, and water, A drug composition in which, depending on the volume of the drug composition, the content of the iodine contrast agent is 208 mg / mL to 624 mg / mL, and the content of the ethanol is 484 mg / mL to 677 mg / mL.
2. The drug composition according to claim 1, wherein the iodine contrast agent is selected from iopromide, iobitridol, iopamidol, iomeprole, iodixanol, ioversol, iohexol, and iotrolane, and is preferably iopromide or iobitridol.
3. The drug composition according to claim 1 or 2, comprising an iodine contrast agent, ethanol, and water.
4. Depending on the volume of the drug composition, the content of the iodine contrast agent is 229 mg / mL to 280 mg / mL. Preferably, the ethanol content of the drug composition is 630 mg / mL to 677 mg / mL, more preferably 630 mg / mL to 658 mg / mL, depending on the volume of the drug composition. Preferably, the water is water for injection, and more preferably, depending on the volume of the drug composition, the water content is at least 29 mg / mL, preferably 30 mg / mL to 125 mg / mL, more preferably 33 mg / mL to 115 mg / mL, and more preferably 70 mg / mL to 115 mg / mL. Preferably, the iodine content of the drug composition is 100 mg / mL to 300 mg / mL, preferably 110 mg / mL to 270 mg / mL, and more preferably 110 mg / mL to 134 mg / mL, depending on the volume of the drug composition. Preferably, the drug composition according to any one of the above claims, wherein, by volume, the iodine contrast agent is iopromide, the iopromide content is 208 mg / mL to 624 mg / mL, and the ethanol content is 484 mg / mL to 677 mg / mL.
5. The drug composition according to any one of the above claims, wherein the iodine contrast agent in the drug composition is completely dissolved, and the drug composition is a homogeneous solution.
6. The drug composition according to any one of the above claims, wherein the drug composition is prepared as an injectable solution.
7. An injectable preparation containing the drug composition according to any one of claims 1 to 6.
8. A method for producing a drug composition according to any one of claims 1 to 6 or an injectable preparation according to claim 7, The present invention comprises adding an iodine contrast agent to water for injection in the content described in any one of claims 1 to 6, stirring while heating until completely dissolved, cooling to 50°C or below, adding anhydrous ethanol and stirring uniformly, filtering, and obtaining the drug composition, and optionally filling the drug composition into a tank, sterilizing, and obtaining the injectable preparation. Preferably, the iodine contrast agent is selected from iopromide, iobitridol, iopamidol, iomeprole, iodixanol, ioversol, iohexol, and iotrolane, and is preferably iopromide or iobitridol, in a method for manufacturing.
9. Use of the drug composition according to any one of claims 1 to 6 or the injectable formulation according to claim 7 in the manufacture of a drug for treating vascular malformations, abdominal cystic diseases, or persistent pain, Preferably, the vascular malformation is a venous malformation, arteriovenous malformation, lymphatic malformation, or mixed malformation, as used.
10. The aforementioned abdominal cystic disease is a liver cyst, kidney cyst, ovarian cyst, or pelvic lymphoid cyst. Preferably, the use according to claim 9, wherein the drug for treating stubborn pain is a drug for nerve destruction.