Iodine contrast agent composition

Abstract

Disclosed in the present application is an iodine contrast agent composition, comprising an iodine contrast agent, ethanol and water. On the basis of the volume of the pharmaceutical composition, the content of the iodine contrast agent is 208-624 mg / mL, and the content of the ethanol is 484-677 mg / mL. The composition has good effects on vascular embolization and in vivo and in vitro imaging, can meet the clinical requirements of image visualization, is clear and uniform in solution and good in stability, and has a good safety, low irritation, and little influence on tissues surrounding a focus.

Description

Iodine contrast agent composition Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to an iodine contrast agent ethanol composition and a preparation method and application thereof. Background Art

[0002] Venous malformations are a common congenital venous malformation with an incidence of 0.01-0.02%, with no significant gender difference. Venous malformations can affect any part of the body, most commonly in the mouth, airway, and head and neck. Severe venous malformations can affect multiple tissues and organs, leading to numerous disabling and potentially fatal complications. For example, venous malformations in the head and neck can cause significant cosmetic disfigurement and functional impairments such as mastication and respiratory obstruction. Venous malformations affecting the limbs and joints often result in severe swelling, pain, joint stiffness, limb dysfunction, and even disability. Some patients may suffer life-threatening complications from localized intravascular coagulation (LIC) or disseminated intravascular coagulation (DIC). The mainstream international treatment for venous malformations is endovascular sclerotherapy. Its primary principle is to damage and destroy vascular endothelial cells through various mechanisms, leading to occlusion of the lesion's sinusoids and fibrosis. However, existing sclerosing agents have distinct advantages and disadvantages, making them inadequate for the diverse and complex treatment of venous malformations.

[0003] An arteriovenous malformation (AVM) is a rare congenital high-flow vascular malformation characterized by abnormal communication between arteries and veins. Its primary manifestation is the direct communication between abnormally communicating arteries and veins in the absence of a normal capillary bed, forming numerous tiny arteriovenous fistulas. AVMs commonly occur on the face, neck, and extremities, and clinically manifest as redness, swelling, heat, and pulsating masses. Most cases are progressive and can develop into severe bleeding, infection, ulceration, necrosis, functional impairment, and even heart failure. Endovascular embolization plays a key role in the treatment of AVMs, enabling better treatment for AVMs previously considered inoperable or with extremely high surgical risks.

[0004] Abdominal cystic diseases often involve organs such as the liver, kidneys, ovaries, and pelvic lymph nodes, with liver, kidney, and ovarian cysts being the most common. Their occurrence is associated with a range of congenital and acquired cystic lesions. Most patients present with no obvious clinical symptoms and typically require no treatment. However, as the cyst enlarges, it may cause symptoms such as abdominal pain and back pain, and may compress and displace adjacent tissues, necessitating prompt treatment. Traditionally, single puncture and drainage were used for treatment, but the recurrence rate of cysts is high, and traditional surgical procedures carry significant risks, seriously impacting patient outcomes. With the advancement of imaging technologies such as computed tomography (CT) and ultrasound, image-guided percutaneous puncture sclerotherapy has gradually replaced surgical procedures. It offers advantages such as minimal invasiveness, minimal pain, repeatability, simplicity, excellent efficacy, and a lower recurrence rate than simple cyst drainage. The principle of sclerotherapy is that a sclerosant, such as anhydrous ethanol, comes into contact with the cyst wall, causing the proteins in the cyst wall to coagulate and denature, disrupting the cells and hardening and closing the cyst wall. This cessation of cystic fluid secretion ultimately results in the cyst being minimized or eliminated.

[0005] Intractable pain refers to persistent pain that is refractory to some or all treatments. It can be categorized by etiology as cancer pain or non-cancer pain. It can occur anywhere in the central and peripheral nervous systems, including the body and viscera. The nature of the pain can be categorized as nociceptive pain or neuropathic pain. For some patients whose intractable pain remains ineffective despite multiple treatments, neurodestructive therapy can be considered, provided the indications are strictly controlled and the patient's informed consent is obtained. Neurodestructive therapy involves the use of chemical agents, radiofrequency thermocoagulation, or surgery to destroy the function of nerves within ganglia, trunks, plexuses, or sheaths to treat intractable pain. The most commonly used drugs in interventional-guided neurodestructive therapy are ethanol (50% to 100%) and phenol (5% to 10%).

[0006] Anhydrous ethanol is a commonly used liquid embolic agent that can quickly destroy vascular endothelial cells and denature hemoglobin, leading to extensive thrombosis and fibrosis in blood vessels, promoting thrombosis of drainage veins and thrombosis in lesions. It can also quickly cause cell dehydration and necrosis, resulting in cyst closure and nerve damage. It is currently widely used in the clinical diagnosis and treatment of cysts, arteriovenous malformations, venous malformations, and nerve damage.

[0007] Iopromide is a non-ionic low-osmolar contrast agent mainly used for computed tomography (CT), arterial / venous digital silhouette angiography (DSA), and endoscopic retrograde cholangiopancreatography (ERCP).

[0008] Anhydrous ethanol and iopromide injection can be used in combination for sclerotherapy under the guidance of CT or digital subtraction angiography (DSA). Traditional CT- or DSA-guided sclerotherapy involves a two-step process: first, after puncture, a contrast agent (iopromide injection) is injected to fill the lesion and determine its location and size. Then, a non-visualizing sclerosant (anhydrous ethanol) is injected into the lesion cavity to replace the original contrast agent. This procedure is relatively cumbersome and time-consuming. Ethanol does not show up on CT or DSA and may overflow from the lesion during treatment, leading to side effects or increased risks.

[0009] The prior art mixes iopromide with anhydrous ethanol and then adds a suspending agent to prepare an iopromide-anhydrous ethanol suspension, thereby improving the cumbersome operating steps of the above-mentioned sclerotherapy. However, the preparation is a suspension and has a greater risk in clinical use.

[0010] Summary of the Invention

[0011] One or more embodiments of the present application provide a pharmaceutical composition comprising an iodine contrast agent, ethanol, and water, wherein 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, based on the volume of the pharmaceutical composition.

[0012] In one or more embodiments, the content of the iodinated contrast agent 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 based on the volume of the pharmaceutical composition.

[0013] In one or more embodiments, the content of ethanol is 500 mg / mL, 550 mg / mL, 600 mg / mL or 650 mg / mL based on the volume of the pharmaceutical composition.

[0014] In one or more embodiments, the iodine contrast agent is selected from iopromide, iobitrol, iopamidol, iomeprol, iodixanol, ioversol, iohexol, and iotrolan.

[0015] In one or more embodiments, the iodine contrast agent is iopromide or iobitrol.

[0016] In one or more embodiments, the pharmaceutical composition consists of an iodinated contrast agent, ethanol, and water.

[0017] In one or more embodiments, the content of the iodinated contrast agent is 229 mg / mL to 280 mg / mL based on the volume of the pharmaceutical composition.

[0018] In one or more embodiments, the content of ethanol is 630 mg / mL to 677 mg / mL based on the volume of the pharmaceutical composition.

[0019] In one or more embodiments, the content of ethanol is 630 mg / mL to 658 mg / mL based on the volume of the pharmaceutical composition.

[0020] In one or more embodiments, the water is water for injection.

[0021] In one or more embodiments, the water content is at least 29 mg / mL based on the volume of the pharmaceutical composition.

[0022] In one or more embodiments, the content of water is 30 mg / mL to 125 mg / mL based on the volume of the pharmaceutical composition.

[0023] In one or more embodiments, 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 based on the volume of the pharmaceutical composition.

[0024] In one or more embodiments, the water content is 33 mg / mL to 115 mg / mL based on the volume of the pharmaceutical composition.

[0025] In one or more embodiments, the water content is 70 mg / mL to 115 mg / mL based on the volume of the pharmaceutical composition.

[0026] In one or more embodiments, the content of iodine is 100 mg / mL to 300 mg / mL based on the volume of the pharmaceutical composition.

[0027] In one or more embodiments, the iodine content is 150 mg / mL, 200 mg / mL, or 250 mg / mL based on the volume of the pharmaceutical composition.

[0028] In one or more embodiments, the iodine content is 110 mg / mL to 270 mg / mL based on the volume of the pharmaceutical composition.

[0029] In one or more embodiments, the iodine content is 110 mg / mL to 134 mg / mL based on the volume of the pharmaceutical composition.

[0030] In one or more embodiments, based on the volume of the pharmaceutical composition, the iodine contrast agent is iopromide, the content of iopromide is 208 mg / mL to 624 mg / mL (e.g., 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 (e.g., 500 mg / mL, 550 mg / mL, 600 mg / mL, or 650 mg / mL).

[0031] In one or more embodiments, the iodine contrast agent is iopromide, and the content of iopromide is 208 mg / mL to 624 mg / mL (e.g., 220 mg / mL, 250 mg / mL, 280 mg / mL, 300 mg / mL, 350 mg / mL, 400 mg / mL, 450 mg / mL, 500 mg / mL, 600 mg / mL, 700 mg / mL, 800 mg / mL, 900 mg / mL, 1000 mg / mL, 1100 mg / mL, 1200 mg / mL, 1300 mg / mL, 1400 mg / mL, 1500 mg / mL, 1600 mg / mL, 1700 mg / mL, 1800 mg / mL, 1900 mg / mL, 2000 mg / mL, 2100 mg / mL, 2200 mg / mL, 2500 mg / mL, 2800 mg / mL, 3000 mg / mL, 3500 mg / mL, 4000 mg / mL, 4500 mg / mL, 5000 mg / mL, 6000 mg / mL, 7000 mg / mL, 8000 mg / mL, 9000 mg / mL, 1800 mg / mL, 1900 mg / mL, The content of the ethanol is 484 mg / mL to 677 mg / mL (e.g., 500 mg / mL, 550 mg / mL, or 600 mg / mL), the content of the water (e.g., water for injection) is at least 29 mg / mL (e.g., 30 mg / mL to 125 mg / mL, specifically, 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).

[0032] In one or more embodiments, the iodinated contrast agent in the pharmaceutical composition is completely dissolved, and the pharmaceutical composition is a homogeneous solution.

[0033] In one or more embodiments, the pharmaceutical composition is prepared as an injection.

[0034] One or more embodiments of the present application provide an injectable preparation comprising the pharmaceutical composition of the present application.

[0035] One or more embodiments of the present application provide a method for preparing the pharmaceutical composition of the present application, which comprises adding an iodine contrast agent to water for injection according to the content described above, heating and stirring until completely dissolved, cooling to below 50°C, adding anhydrous ethanol and stirring evenly, and filtering to obtain the pharmaceutical composition.

[0036] One or more embodiments of the present application provide a method for preparing the injectable preparation of the present application, which comprises filling and sterilizing the pharmaceutical composition of the present application to obtain the injectable preparation.

[0037] In one or more embodiments, the iodine contrast agent is selected from the group consisting of iopromide, iobitrol, iopamidol, iomeprol, iodixanol, ioversol, iohexol, and iotrolan.

[0038] In one or more embodiments, the iodine contrast agent is iopromide or iobitrol.

[0039] One or more embodiments of the present application provide use of the pharmaceutical composition or the injectable formulation of the present application in preparing a drug for treating vascular malformations, abdominal cystic diseases, or intractable pain.

[0040] In one or more embodiments, the vascular malformation is a venous malformation, an arteriovenous malformation, a lymphatic malformation, or a mixed malformation.

[0041] In one or more embodiments, the abdominal cystic disease is a liver cyst, a kidney cyst, an ovarian cyst, or a pelvic lymphocele.

[0042] In one or more embodiments, the drug for treating intractable pain is a drug for nerve damage.

[0043] One or more embodiments of the present application provide the pharmaceutical composition or injection preparation of the present application, which is used as a medicine.

[0044] One or more embodiments of the present application provide a pharmaceutical composition or injectable formulation of the present application, which is used to treat vascular malformations, abdominal cystic diseases, or intractable pain.

[0045] One or more embodiments of the present application provide a method for treating vascular malformations, abdominal cystic diseases, or intractable pain, comprising administering the pharmaceutical composition or injectable formulation of the present application to a subject in need thereof.

[0046] In one or more embodiments, the vascular malformation is a venous malformation, an arteriovenous malformation, a lymphatic malformation, or a mixed malformation.

[0047] In one or more embodiments, the abdominal cystic disease is a liver cyst, a kidney cyst, an ovarian cyst, or a pelvic lymphocele.

[0048] In one or more embodiments, the drug used to treat intractable pain is a drug for nerve damage.

[0049] In one or more embodiments, in the pharmaceutical composition, the iodine contrast agent is iopromide in an amount of 229-280 mg / mL, the ethanol in an amount of 630-677 mg / mL, and the water for injection in an amount of 33-115 mg / mL.

[0050] In one or more embodiments, in the pharmaceutical composition, the iodine contrast agent is iopromide in an amount of 229 mg / mL, the ethanol in an amount of 630 mg / mL to 658 mg / mL, and the water for injection in an amount of 70 mg / mL to 115 mg / mL.

[0051] The present invention provides an iodine contrast agent-ethanol pharmaceutical composition, comprising an iodine contrast agent, ethanol, and water for injection, wherein the proportion of ethanol is 484 mg / mL to 677 mg / mL, the proportion of the iodine contrast agent is greater than or equal to 208 mg / mL, and the proportion of the water for injection is greater than 29 mg / mL;

[0052] Furthermore, the composition is a homogeneous solution, and the iodine contrast agent is completely dissolved in the composition;

[0053] Furthermore, the iodine contrast agent is selected from iopromide, iobitrol, iopamidol, iomeprol, iodixanol, ioversol, iohexol, and iotrolan, preferably iopromide or iobitrol.

[0054] The present invention also provides an iodine contrast agent-ethanol pharmaceutical composition, which consists of an iodine contrast agent, ethanol, and water for injection, wherein the proportion of ethanol is 484 mg / mL to 677 mg / mL, the proportion of the iodine contrast agent is greater than or equal to 208 mg / mL, and the proportion of the water for injection is greater than 29 mg / mL. The composition is a homogeneous solution, and the iodine contrast agent is completely dissolved in the composition; further, the iodine contrast agent is selected from iopromide, iobitrol, iopamidol, iomeprol, iodixanol, ioversol, iohexol, iotrolan, and ethiodized oil of papaver, and is preferably iopromide or iobitrol.

[0055] Furthermore, in the iodine contrast agent-ethanol pharmaceutical composition provided by the present invention, the proportion of the iodine contrast agent is preferably 208 mg / mL to 624 mg / mL, more preferably 229 mg / mL to 280 mg / mL.

[0056] Furthermore, the present invention provides an iodine contrast agent-ethanol pharmaceutical composition, wherein the iodine content of the composition is preferably 100 mg / mL to 300 mg / mL, more preferably 110 mg / mL to 270 mg / mL, and the iodine content of certain specific compositions of the present invention is also preferably 110 mg / mL to 134 mg / mL.

[0057] Furthermore, in the iodine contrast agent-ethanol pharmaceutical composition provided by the present invention, the proportion of ethanol is preferably 630 mg / mL to 677 mg / mL, more preferably 630 mg / mL to 658 mg / mL.

[0058] Furthermore, in the iodine contrast agent-ethanol pharmaceutical composition provided by the present invention, the proportion of water for injection is preferably 30 mg / mL to 125 mg / mL, more preferably 33 mg / mL to 115 mg / mL. The proportion of water for injection in certain specific compositions of the present invention is also preferably 70 mg / mL to 115 mg / mL.

[0059] Furthermore, in the iodine contrast agent-ethanol pharmaceutical composition provided by the present invention, the iodine contrast agent is preferably iopromide at a ratio of 229 to 280 mg / mL, the ethanol is preferably at a ratio of 630 mg / mL to 677 mg / mL, and the water for injection is preferably at a ratio of 33 mg / mL to 115 mg / mL.

[0060] Furthermore, in the iodine contrast agent-ethanol pharmaceutical composition provided by the present invention, the iodine contrast agent is preferably iopromide at a ratio of 229 mg / mL, the ethanol ratio is preferably 630 mg / mL to 658 mg / mL, and the water for injection ratio is preferably 70 mg / mL to 115 mg / mL.

[0061] The present invention also provides a method for preparing an iodine contrast agent-ethanol pharmaceutical composition, which is characterized by: adding the iodine contrast agent raw material to water for injection according to the above prescription ratio, heating until completely dissolved, cooling the solution to below 50°C, adding anhydrous ethanol, stirring evenly, filtering, filling, and sterilizing.

[0062] On the other hand, the present invention provides use of the above-mentioned pharmaceutical composition in the preparation of a method for treating vascular malformations such as venous malformations, arteriovenous malformations, lymphatic malformations, and mixed malformations.

[0063] Furthermore, the use is the use of the drug in the treatment of venous malformations, arteriovenous malformations, abdominal cystic diseases, liver cysts, kidney cysts, ovarian cysts, pelvic lymphoceles and nerve damage for intractable pain.

[0064] In one or more embodiments, the pharmaceutical composition of the present application is in a solution state, and is a clear solution with uniform appearance and stable properties.

[0065] In one or more embodiments, the pharmaceutical composition of the present application has good solution stability, and no solid precipitation is observed under conditions such as vigorous shaking and open storage.

[0066] In one or more embodiments, the pharmaceutical composition of the present application has good imaging effects in vivo and in vitro, and achieves good imaging effects with a relatively low content of iodine contrast agent (such as iopromide).

[0067] In one or more embodiments, the pharmaceutical composition of the present application satisfies the clinical therapeutic effect of vascular embolization and achieves the purpose of visualized embolization therapy.

[0068] In one or more embodiments, the pharmaceutical composition of the present application achieves in vivo and in vitro imaging effects, blood vessels can be clearly distinguished by the naked eye, and the vascular embolization effect can meet the clinical treatment effect.

[0069] In one or more embodiments, the pharmaceutical composition of the present application has few side effects.

[0070] In one or more embodiments, the pharmaceutical composition of the present application causes less damage to surrounding tissues than anhydrous ethanol.

[0071] In one or more embodiments, the pharmaceutical composition of the present application has a good vascular embolization effect, has a good in vitro and in vivo DSA imaging effect, improves the accuracy of vascular embolization treatment, and achieves a better treatment effect.

[0072] In one or more embodiments, while improving the accuracy of vascular embolization treatment, the pharmaceutical composition of the present application causes significantly less damage to surrounding tissues than anhydrous ethanol, and does not significantly increase the degree of proliferation and / or necrosis of surrounding tissues.

[0073] In one or more embodiments, the pharmaceutical composition of the present application further improves the therapeutic effect, reduces the contrast agent content, reduces the cost of use, and reduces potential clinical risks while ensuring low irritation and low adverse reactions.

[0074] In one or more embodiments, the pharmaceutical composition of the present application (e.g., iopromide-ethanol pharmaceutical composition, iobitrol-ethanol pharmaceutical composition) can be dynamically monitored during the treatment process, and imaging and treatment can be completed with just one injection, thereby improving the cumbersome problems of traditional DSA-guided technology and sclerotherapy performed in steps, and the treatment is accurate, effective, and has a low adverse reaction rate.

[0075] In one or more embodiments, compared with traditional DSA-guided sclerotherapy technology, the pharmaceutical composition of the present application reduces the cumbersome operations caused by the two-step injection of treatment and imaging, and only one-step injection is needed to complete treatment and imaging, thereby achieving the purpose of dynamic monitoring during the treatment process.

[0076] In one or more embodiments, the pharmaceutical composition of the present application has higher therapeutic accuracy and less side effects, is less irritating, and has higher safety and stability.

[0077] In one or more embodiments, the iodine contrast agent content of the pharmaceutical composition of the present application is much lower than that of the mainstream commercially available iopromide injection. The use of a lower content of iodine contrast agent achieves a good imaging effect, lower usage cost, and less clinical risk.

[0078] In one or more embodiments, the pharmaceutical composition of the present application has one or more of the following good technical effects: good angioembolization effect; good in vivo and in vitro DSA development effect; able to meet the clinical needs of "visualization" of images; the solution is clear, uniform, and stable; good safety, low irritation, and little effect on the tissues around the lesion, for example, no tissue hyperplasia and / or necrosis occurs. BRIEF DESCRIPTION OF THE DRAWINGS

[0079] FIG1 shows the in vitro imaging effects of Examples 5 to 7 and the commercially available preparation Uvizine 300.

[0080] FIG2 shows the in vivo imaging effects of Example 1, the commercially available preparation Uvizine 300, and normal saline.

[0081] FIG. 3 shows the in vivo imaging effects of Example 1 and Comparative Example C in Experimental Example 3. DETAILED DESCRIPTION

[0082] The following examples illustrate the present application, but the protection scope of the present application is not limited to the following examples.

[0083] Preparation Example 1

[0084] The prescription composition of iodine contrast agent-ethanol injection is shown in Table 1.

[0085] Table 1

[0086] The preparation method is as follows: add the prescribed amount of water for injection to a dispensing tank, slowly add the prescribed amount of iopromide, stir under heating until completely dissolved, cool the solution to below 50°C, add the prescribed amount of anhydrous ethanol, and stir evenly. Filter, fill, and sterilize to obtain iopromide-ethanol injection.

[0087] Preparation Example 2

[0088] With reference to the preparation method of Example 1, the iodine contrast agent-ethanol injections of Examples 2 to 9 were prepared according to the prescriptions in Table 2 below.

[0089] Table 2

[0090] The iodine contrast agent-ethanol injections prepared in Examples 1 to 9 were all homogeneous, clear solutions. Each 10 mL sample was taken and allowed to stand after vigorous shaking for 30 min, and each sample solution remained homogeneous and clear. Experiments have shown that a pharmaceutical composition comprising an iodine contrast agent, ethanol, and water for injection (e.g., 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 produce a homogeneous, stable, clear solution composition.

[0091] Comparative Examples A to D

[0092] Referring to the preparation method in Example 1, iodine contrast agent-ethanol injection was prepared according to the prescription composition in Table 3.

[0093] Table 3

[0094] Comparative Examples A to D all gave homogeneous and clear solutions. 10 mL of each sample was taken and shaken vigorously for 30 minutes and then allowed to stand. The sample solutions remained homogeneous and clear.

[0095] Comparative Example E

[0096] Iodine contrast agent-ethanol injection was prepared according to the prescription composition in Table 4.

[0097] Table 4

[0098] The preparation method was the same as in Example 1. After adding 68.22 g of anhydrous ethanol to the volume, the solution became slightly turbid. A 10 mL sample was shaken vigorously for 30 minutes and then allowed to stand, and the turbidity became even more pronounced. This indicates that Comparative Example E failed to produce a uniform, clear iodine contrast agent-ethanol solution.

[0099] Comparative Example F

[0100] 20 g of iopromide powder was dispersed in 50 mL (39.47 g) of anhydrous ethanol and shaken to obtain an iopromide-anhydrous ethanol suspension. 0.05 g of Tween 80 was added to the suspension, shaken to uniformly disperse it, and then anhydrous ethanol was added to make the volume to 100 mL to obtain an iopromide-anhydrous ethanol suspension injection.

[0101] Comparative Example G

[0102] 25 mL of commercially available iopromide injection (containing 0.769 g / mL of iopromide) was rotary evaporated to remove the solvent to obtain a powder. 25 mL (19.73 g) of anhydrous ethanol was then added and pre-dispersed by ultrasonication for 20 minutes. The pre-dispersed mixture was then placed in a reactor and pressurized to 15 MPa using supercritical carbon dioxide at 40°C and 1000 rpm / min for 2 hours. Finally, the mixture was depressurized to atmospheric pressure to obtain an iopromide-ethanol solution. A 10 mL sample was vigorously shaken for 30 minutes and then allowed to stand. The sample solution became slightly turbid.

[0103] Experimental Example 1a

[0104] In vitro imaging of Examples 5 to 7 and the commercially available iopromide injection (Ultravisant 300) was performed using an INFX-9000C digital subtraction angiography machine (DSA) (manufacturer: Canon). The imaging results are shown in FIG1 .

[0105] The imaging results show that the in vitro imaging depth of the iopromide-ethanol injection obtained in Examples 5 to 7 under DSA is not significantly different from that of the commercially available preparation (Ultravis 300). The applicant has experimentally discovered that the pharmaceutical composition provided by the present invention comprising an iodine contrast agent, ethanol, and water for injection (e.g., 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 good in vitro imaging effects, achieving good imaging effects with a lower content of iopromide.

[0106] Experimental Example 1b

[0107] 2 mL each of normal saline, commercially available iopromide injection (Ultravis 300), and the iodine contrast agent-ethanol injection of Example 1 were injected into the bilateral renal arteries of New Zealand rabbits within 10 seconds. The images were then visualized in vivo under DSA. The imaging results are shown in Figure 2.

[0108] The imaging results show that the blood vessels of the kidneys are clearly visible under DSA, and the iopromide-ethanol injection obtained in Example 1 can display images of animal organs that are distinguishable to the naked eye. The applicant has discovered through experiments that the pharmaceutical composition of the present application comprising an iodine contrast agent, ethanol, and water for injection (e.g., 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 good in vivo imaging effects and can meet the clinical demand for "visualization" of images.

[0109] Experimental Example 2

[0110] Eighteen New Zealand rabbits were divided into three groups of six. Each group was administered drugs via slow injection into the right marginal auricular vein: 1 mL of normal saline, 1 mL of anhydrous ethanol, and 1 mL of the iopromide-ethanol injection described in Example 1, respectively. After the injections, the needles were removed and the injection sites were marked. The rabbits were observed for 14 days after administration, and ear tissue was collected for case staining. The degree of vascular embolism was graded: no embolism, grade "0"; partial embolism, grade "I"; and complete embolism, grade "II." At the same time, a graded evaluation is made according to the degree of damage to the surrounding tissues: no lesions are seen in the perivascular tissues, graded "0"; there is no or slight increase in perivascular inflammatory cells, mild hyperplasia of granulation tissue, and no obvious tissue thickening, graded "I"; there is a slight increase in perivascular inflammatory cells, obvious hyperplasia of granulation tissue, and visible tissue thickening, graded "II"; there is partial necrosis in the perivascular tissues, and the necrotic area is less than 1 / 3 of the tissue section, graded "III"; there is extensive necrosis in the perivascular tissues, and the necrotic area occupies 1 / 3 or more of the tissue, graded "IV".

[0111] The experimental results of vascular embolism and surrounding tissue damage in the three groups of experiments are shown in Table 5.

[0112] Table 5

[0113] In the table, N represents the number of animals in each group. The differences between the groups were analyzed using the chi-square test. " / " means not applicable or there was no statistically significant difference between the group and other groups. P < 0.05 represents a significant difference.

[0114] According to the above exemplary experimental results, there is no significant difference in the vascular embolization effect caused by the iopromide-ethanol injection of Example 1 and anhydrous ethanol, and the embolization effect is slightly better than that of anhydrous ethanol in terms of the incidence of complete embolism. This shows that the iopromide-ethanol injection of the present application has a good vascular embolization effect and can meet the needs of clinical treatment of venous malformations. The degree of damage to surrounding tissues in Example 1 is significantly lower than that of anhydrous ethanol, and compared with anhydrous ethanol, it has fewer side effects and higher treatment accuracy.

[0115] Experimental Example 3

[0116] 40 New Zealand rabbits were divided into 10 groups of 4 rabbits each. Each group of New Zealand rabbits was slowly injected into the right marginal ear vein, with 1 mL of iopromide-ethanol injection obtained from Example 1, Example 3, Example 4, Example 6, Comparative Example A, Comparative Example B, Comparative Example C, Comparative Example D, and Comparative Example F being injected into each group. After the injection, the needle was removed, the injection site was marked, and each group of animals was imaged in vivo under DSA, and the DSA imaging intensity value was recorded. The animals were then observed for 14 days, and ear tissue was obtained for case staining. Each animal was scored according to the degree of vascular embolism: no embolism, score 0; partial embolism, score 1; complete embolism, score 2. At the same time, each animal was scored according to the degree of damage to the surrounding tissues: no lesions were found in the perivascular tissues, score 0; no or slight increase in perivascular inflammatory cells, mild hyperplasia of granulation tissue, and no obvious thickening of the tissues, score 1; slight increase in perivascular inflammatory cells, obvious hyperplasia of granulation tissue, and visible thickening of the tissues, score 2; partial necrosis of the perivascular tissues, with the necrotic area less than 1 / 3 of the tissue section, score 3; extensive necrosis of the perivascular tissues, with the necrotic area accounting for 1 / 3 or more of the tissue section, score 4. The average value of the degree of vascular embolism and the degree of surrounding tissue damage in each group of animals was used as the venous occlusion pathology score and the surrounding tissue damage pathology score. Figure 3 is a diagram of the development effect of the iopromide-ethanol injection of Example 1 and Comparative Example C. The experimental results of each group are shown in Table 6.

[0117] Table 6

[0118] “ / ” means not detected.

[0119] According to the results of the above exemplary experiments, the venous occlusion pathology scores of Comparative Examples A and B were less than 0.5, indicating poor venous occlusion effects; the surrounding tissue damage pathology scores of Comparative Examples C, D, and F were greater than or equal to 1.5, indicating significant surrounding tissue necrosis and obvious side effects. In addition, the DSA imaging intensity of Comparative Examples C, D, and F was weak, making it difficult to distinguish the vascular conditions with the naked eye.

[0120] The above experiments show that DSA has good imaging effects in vivo and in vitro, the naked eye can distinguish blood vessels in the body, the vascular embolization effect is stronger, meeting the requirements of clinical precision treatment, and has fewer side effects. The damage to surrounding tissues is far less than that of anhydrous ethanol, and the degree of hyperplasia and necrosis does not increase significantly.

[0121] Experimental Example 4

[0122] The samples prepared in Example 1, Example 3, Example 4, and Comparative Example G were placed in an open air and at room temperature to investigate the stability of each sample solution. The results are shown in Table 7.

[0123] Table 7

[0124] According to the above exemplary experiments, when comparative example G is placed in the open, there is a more obvious stability problem. The iopromide-ethanol injection of the present application has better storage stability than comparative example G. The above experiments show that the pharmaceutical composition of the present application comprising an iodine contrast agent, ethanol, and water for injection (for example, the content of ethanol is 484mg / mL to 677mg / mL, and the content of iodine contrast agent is 208mg / mL to 624mg / mL) is still not easy to precipitate solids when placed in the open, and has good solution stability.

Claims

1. A pharmaceutical composition comprising an iodine contrast agent, ethanol and water, wherein 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 based on the volume of the pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the iodine contrast agent is selected from iopromide, iobitrol, iopamidol, iomeprol, iodixanol, ioversol, iohexol, and iotrolan; preferably iopromide or iobitrol.

3. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition consists of an iodine contrast agent, ethanol and water.

4. A pharmaceutical composition according to any one of the preceding claims, wherein Based on the volume of the pharmaceutical composition, the content of the iodine contrast agent is 229 mg / mL to 280 mg / mL; Preferably, based on the volume of the pharmaceutical composition, the content of ethanol is 630 mg / mL to 677 mg / mL, preferably 630 mg / mL to 658 mg / mL; Preferably, the water is water for injection; more preferably, based on the volume of the pharmaceutical composition, the content of the water is at least 29 mg / mL; preferably, the content of the water is 30 mg / mL to 125 mg / mL, preferably 33 mg / mL to 115 mg / mL, more preferably 70 mg / mL to 115 mg / mL; Preferably, based on the volume of the pharmaceutical composition, the iodine content is 100 mg / mL to 300 mg / mL, preferably 110 mg / mL to 270 mg / mL, more preferably 110 mg / mL to 134 mg / mL; Preferably, based on the volume of the pharmaceutical composition, the iodine contrast agent is iopromide, the content of iopromide is 208 mg / mL to 624 mg / mL, and the content of ethanol is 484 mg / mL to 677 mg / mL.

5. The pharmaceutical composition according to any one of the preceding claims, wherein the iodinated contrast agent in the pharmaceutical composition is completely dissolved and the pharmaceutical composition is a homogeneous solution.

6. The pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition is prepared as an injection.

7. An injection preparation comprising the pharmaceutical composition according to any one of claims 1 to 6.

8. A method for preparing the pharmaceutical composition according to any one of claims 1 to 6 or the injection preparation according to claim 7, comprising adding an iodine contrast agent according to the content according to any one of claims 1 to 6 to water for injection, heating and stirring until completely dissolved, cooling to below 50° C., adding anhydrous ethanol and stirring evenly, filtering to obtain the pharmaceutical composition; optionally, filling and sterilizing the pharmaceutical composition to obtain the injection preparation; Preferably, the iodine contrast agent is selected from iopromide, iobitrol, iopamidol, iomeprol, iodixanol, ioversol, iohexol and iotrolan; preferably, the iodine contrast agent is iopromide or iobitrol.

9. Use of the pharmaceutical composition according to any one of claims 1 to 6 or the injection preparation according to claim 7 in the preparation of a medicament for treating vascular malformations, abdominal cystic diseases, or intractable pain; preferably, the vascular malformation is a venous malformation, an arteriovenous malformation, a lymphatic malformation, or a mixed malformation.

10. The use according to claim 9, wherein the abdominal cystic disease is a liver cyst, a kidney cyst, an ovarian cyst, or a pelvic lymphocyst; preferably, the drug for treating intractable pain is a drug for nerve damage.

Images