Iopromide-ethanol composition as well as preparation method and application thereof

Abstract

The invention provides an iopromide-ethanol composition as well as a preparation method and application thereof, and relates to the technical field of medicines. The iopromide-ethanol composition provided by the invention is an injection and consists of iopromide, ethanol and water for injection, the liquid medicine can be used for treating vascular deformity, lymphatic vessel deformity, mixed deformity and the like, tedious operation caused by two-step injection of treatment and radiography is reduced, treatment and development can be completed only through one-step injection, the purpose of dynamic monitoring in the treatment process is achieved, and compared with suspension liquid, the liquid medicine has the advantages of higher treatment precision, smaller side effect, smaller irritation and lower cost. The stability is higher, and the clinical safety can be effectively ensured.

Description

Technical Field

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

[0002] 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, tumor cell necrosis, nerve damage, etc. It is currently widely used in clinical diagnosis and treatment of tumor treatment, interventional treatment of body cysts, arteriovenous malformations and venous malformations, VOM ablation, HOCM ventricular septal ablation, nerve damage treatment, etc.

[0003] Iopromide is a non-ionic low-osmolar contrast agent, mainly used for computerized tomography (CT), arterial / venous digital silhouette angiography (DSA), and endoscopic retrograde cholangiopancreatography (ERCP). Anhydrous ethanol and iopromide can be used in combination for sclerotherapy under the guidance of digital subtraction angiography (DSA). Traditional CT or DSA-guided sclerotherapy technology is divided into two steps. First, the contrast agent (iopromide injection) is injected after puncture to fill the lesion and clarify the location and size of the lesion. Then, the non-visible sclerosing agent (anhydrous ethanol) is injected into the lesion cavity to replace the original contrast agent. The steps are relatively cumbersome and time-consuming. Ethanol does not show up under CT or DSA, and may overflow from the lesion during treatment, resulting in side effects or increased risks.

[0004] In the prior art, iopromide is mixed with anhydrous ethanol and then a suspending agent is added to prepare an iopromide-anhydrous ethanol suspension, thereby improving the cumbersome operation steps of the above-mentioned sclerotherapy. However, the preparation is a suspension and has a relatively high risk in clinical use. Summary of the invention

[0005] One of the purposes of the present invention is to provide an iopromide-ethanol composition, which simplifies the injection steps, reduces the treatment time and reduces the clinical risks.

[0006] Another object of the present invention is to provide a method for preparing an iopromide-ethanol composition, which is used to prepare the above-mentioned iopromide-ethanol composition.

[0007] Another object of the present invention is to provide use of the iopromide-ethanol composition in preparing a pharmaceutical preparation.

[0008] The technical solution adopted by the present invention is as follows:

[0009] The invention discloses an iopromide-ethanol composition, which is an injection, and is composed of iopromide, ethanol and water for injection; wherein the concentration of iopromide is not less than 208 mg / ml (that is, the concentration of iodine is not less than 100 mg / mL), the concentration of ethanol is 480 mg / ml-680 mg / ml, and the concentration of water for injection is 30 mg / ml-150 mg / ml; and in the iopromide, the content of E1 configuration is 8.0%-12.0%, the content of E2 configuration is 9.0%-14.0%, the content of Z1 configuration is 36%-40%, and the content of Z2 configuration is 38%-44%.

[0010] In a preferred embodiment of the present invention, the iopromide is completely dissolved in the liquid phase to form a true solution.

[0011] In a preferred embodiment of the present invention, the concentration of iopromide is 208 mg / ml to 630 mg / ml, preferably 229 mg / ml to 280 mg / ml, and more preferably 229 mg / ml to 250 mg / ml.

[0012] In a preferred embodiment of the present invention, the ethanol concentration is 630 mg / mL to 677 mg / mL, preferably 630 mg / mL to 657 mg / mL.

[0013] In a preferred embodiment of the present invention, the concentration of the water for injection is 33 mg / ml to 130 mg / ml, preferably 35 mg / ml to 125 mg / ml.

[0014] In a preferred embodiment of the present invention, in the iopromide, the content of E1 configuration is 8.0% to 10.0%, the content of E2 configuration is 9.0% to 12.0%, the content of Z1 configuration is 38% to 40%, and the content of Z2 configuration is 40-43%.

[0015] A preparation method of an iopromide-ethanol composition comprises the following steps: adding a prescribed amount of iopromide to a prescribed amount of water for injection, heating until completely dissolved and keeping the temperature, cooling the solution to below 50°C after the temperature is kept, adding anhydrous ethanol, stirring evenly, filtering and filling.

[0016] In a preferred embodiment of the present invention, the temperature is heated to not less than 90° C. and kept warm for 1 h to 6 h; preferably, the temperature is heated to 90° C. to 100° C. and kept warm for 2 h to 4 h.

[0017] It should be noted that the iopromide-ethanol composition of the present invention can select a suitable method for ensuring sterility according to actual needs, such as aseptic preparation, filtration sterilization, high temperature sterilization, etc., and those skilled in the art can refer to the corresponding standards in the prior art for related operations, which have little effect on the performance of the product of the invention and are not specifically limited in the present invention.

[0018] The invention discloses use of an iopromide-ethanol composition in preparing a pharmaceutical preparation, wherein the pharmaceutical preparation is used for treating vascular malformations, lymphatic malformations or mixed malformations.

[0019] In a preferred embodiment of the present invention, the pharmaceutical preparation is used to treat venous malformations, arteriovenous malformations, abdominal cysts, liver cysts, kidney cysts, ovarian cysts or pelvic lymphocys; or is used in tumor interventional embolization and sclerosis therapy, atrial fibrillation ablation therapy, ventricular septal ablation therapy for hypertrophic obstructive cardiomyopathy or nerve destruction therapy for intractable pain.

[0020] The beneficial effects of the present invention are:

[0021] 1. Compared with the traditional DSA-guided sclerotherapy technology, the iodine-promide-ethanol injection of the present invention reduces the cumbersome operation caused by the two-step injection of treatment and imaging, and only requires one-step injection to complete the treatment and imaging, thus achieving the purpose of dynamic monitoring during the treatment process.

[0022] 2. The iopromide-ethanol injection of the present invention is a uniform solution preparation, has higher treatment accuracy and less side effects, is less irritating, and is safer.

[0023] 3. The iopromide-ethanol injection of the present invention has a concentration lower than that of the mainstream iopromide injection on the market, so that a good imaging effect can be achieved by using a lower concentration of iodine contrast agent, with lower use costs and less clinical risks.

[0024] 4. The iopromide-ethanol injection of the present invention has high stability, and iopromide does not precipitate, which can effectively ensure quality uniformity and further ensure clinical safety. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 The in vitro imaging effects of Examples 5-6 and the commercially available preparation Uvizin 300;

[0026] Figure 2 Example 1, commercially available preparation Uvizin 300, in vivo imaging effect of normal saline;

[0027] Figure 3 The development effect diagram of Example 1 and Comparative Example C. DETAILED DESCRIPTION

[0028] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention.

[0029] Example 1

[0030] The prescription composition of iopromide-ethanol injection is shown in Table 1.

[0031] Table 1 The prescription composition of iopromide-ethanol injection in Example 1

[0032] name Prescription amount Preparation amount Iopromide 229mg 22.9kg Anhydrous ethanol 632mg 63.2kg Water for injection 112mg 11.2kg Total injection volume 1mL 100L

[0033] The preparation method is as follows:

[0034] 1. Liquid preparation: Add 11.2 kg of water for injection into the liquid preparation tank and heat to 90°C. Slowly add 22.9 kg of iopromide and stir until completely dissolved. After dissolution, continue stirring and keep warm at 90°C for 2 hours.

[0035] 2. Volume adjustment: Cool the solution to below 50°C, add 63.2 kg of anhydrous ethanol, and stir evenly to obtain iopromide-ethanol solution.

[0036] 3. Filter and bottle the solution.

[0037] Embodiment 2-8

[0038] Referring to the preparation method of Example 1, the iopromide-ethanol injection of Examples 2-8 was prepared according to the prescription shown in Table 2.

[0039] Table 2 Prescription composition of iopromide-ethanol injection in Example 2-8

[0040]

[0041] According to the prescriptions provided in Examples 1-8, the iopromide-ethanol injection obtained by the preparation method provided in Example 1 is a true solution, that is, iopromide is completely dissolved in the liquid phase to form a uniform and clear solution. The applicant has found through experiments that the iopromide-ethanol injection provided by the present invention can obtain a uniform and clear solution when the ethanol concentration is about 480 mg / mL to 680 mg / mL, the iopromide concentration is not less than 208 mg / mL, and the water concentration is not less than 30 mg / mL.

[0042] Comparative Examples A to D

[0043] Referring to the preparation method of Example 1, iopromide-ethanol injection was prepared according to the prescription composition of Table 3.

[0044] Table 3 Prescription composition of iopromide-ethanol injection in comparative examples AD

[0045]

[0046]

[0047] According to the prescriptions provided in Comparative Examples AD and the preparation method provided in Example 1, the iopromide-ethanol injection obtained is also a homogeneous and clear solution.

[0048] Comparative Example E

[0049] Iopromide-ethanol injection was prepared according to the prescription composition in Table 4.

[0050] Table 4 Prescription composition of iopromide-ethanol injection in comparative example E

[0051] name Prescription amount Preparation amount Iopromide 229mg 22.90g Anhydrous ethanol 682.2mg 68.22g Water for injection 28.6mg 2.86g Total injection volume 1mL 100mL

[0052] The preparation method was the same as that of Example 1. After adding 68.22 g of anhydrous ethanol to make up the volume, iopromide precipitated and the solution became slightly turbid. This prescription could not produce a uniform and clear iopromide-ethanol injection.

[0053] Comparative Example F

[0054] 20 g of iopromide powder was dispersed in 50 mL (39.47 g) of anhydrous ethanol, and the mixture was shaken to obtain an iopromide-anhydrous ethanol suspension. 0.05 g of Tween 80 was added to the suspension, and the mixture was shaken to make it uniformly dispersed. The remaining anhydrous ethanol was then added to make the volume to 100 mL to obtain an iopromide-anhydrous ethanol suspension injection.

[0055] Comparative Example G

[0056] 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 min; the pre-dispersed mixed solution was then placed in a reactor, pressurized to 15 MPa with supercritical carbon dioxide, maintained at a temperature of 40°C and a speed of 1000 rpm / min for 2 h, and finally decompressed to a normal pressure environment to obtain an iopromide-ethanol solution. The obtained iopromide-ethanol solution was left open for 24 h, and it was seen that the solution was slightly turbid and iopromide was precipitated.

[0057] Examples 9-15

[0058] According to the prescription composition of Table 1, iopromide-ethanol injection was prepared under the process conditions shown in Table 5, and the prepared iopromide-ethanol injection was allowed to stand to investigate the stability of the product under each process condition. The specific process conditions and the results of the product stability investigation are shown in Table 5.

[0059] Table 5 Process conditions and stability investigation results in Examples 9-15

[0060]

[0061] It is found in the research and development process that the homogeneous clear solution prepared will have stability problems during placement, that is, iopromide is separated out from the solution. Further research finds that the stability of the product is related to the content of the different isomers of iopromide, and it is known that iopromide has four isomers of E1, E2, Z1 and Z2. As shown in Table 5, the iopromide-ethanol injection obtained in Example 9 is left standing for less than 8h and just begins to separate out iopromide, the iopromide-ethanol injection obtained in Example 10-11 is left standing for less than 24h and also has iopromide separated out, and the iopromide-ethanol injection obtained in Example 12-15 can be stably stored for 24h without separating out iopromide. The iopromide-ethanol injection in different embodiments was measured, and it was found that the contents of the four isomers of iopromide in the iopromide-ethanol injection obtained in Examples 12-15 all satisfied the following conditions: 8%<E1<10%, 9%<E2<12%, 38%<Z1<40%, 40%<Z2<43%. In this case, its stability was significantly improved.

[0062] Experimental Example 1a

[0063] Using INFX-9000C digital subtraction angiography (DSA) (manufacturer: Canon), Examples 5-6 and commercially available iopromide injection (Ultravist 300) were imaged in vitro. The image development results are shown in the attached Figure 1 . According to the development results, it can be seen that the in vitro development depth of the iopromide-ethanol injection obtained in Examples 5-6 under DSA is not significantly different from that of the commercially available preparation (Uvix 300). The applicant has found through experiments that the iopromide-ethanol injection provided by the present invention has a good in vitro development effect when the iopromide concentration is not less than 208 mg / mL, and achieves a good development effect with a lower concentration of iopromide.

[0064] Experimental Example 1b

[0065] 2 mL of physiological saline, commercially available iopromide injection (Ulvison 300), and Example 1 were injected into the bilateral renal arteries of New Zealand rabbits, and the injection was completed within 10 seconds. In vivo imaging was performed under DSA. The imaging results are shown in the attached Figure 2 . According to the development results, it can be seen that the blood vessels of the kidney are clearly visible under DSA, and the iopromide-ethanol injection obtained in Example 1 can display animal organ images that can be distinguished by the naked eye. The applicant has found through experiments that the iopromide-ethanol injection provided by the present invention has a good in vitro development effect when the iopromide concentration is not less than 208 mg / mL, which can meet the clinical demand for "visualization" of images.

[0066] Experimental Example 2

[0067] 18 New Zealand rabbits were divided into three groups, 6 in each group, and the right ear vein of each group of New Zealand rabbits was slowly injected with 1 mL of normal saline, 1 mL of absolute ethanol, and 1 mL of iopromide-ethanol injection obtained in Example 1. After the injection, the injection needle was pulled out and the injection site was marked. After the administration, the ear tissue was observed for 14 days, and the case was stained. The vascular embolism degree was graded and evaluated: no embolism, grade "0"; partial embolism, grade "I"; complete embolism, grade "II". At the same time, the surrounding tissue damage was graded and evaluated: no lesions were found in the perivascular tissue, graded "0"; no or slight increase in perivascular inflammatory cells, mild hyperplasia of granulation tissue, no obvious thickening of tissue, graded "I"; slight increase in perivascular inflammatory cells, obvious hyperplasia of granulation tissue, and visible thickening of tissue, graded "II"; partial necrosis was seen in the perivascular tissue, and the necrosis area was less than 1 / 3 of the tissue section, graded "III"; extensive necrosis of the perivascular tissue, and the necrosis area accounted for 1 / 3 or more of the tissue, graded "IV". The experimental results of vascular embolism and surrounding tissue damage in the three groups are shown in Table 6.

[0068] Table 6 Experimental results of vascular embolism and surrounding tissue damage

[0069]

[0070] In the table, N represents the number of animals in each group. The differences among 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.

[0071] It can be seen from the experimental results that there is no significant difference in the vascular embolism effect caused by the iopromide-ethanol injection of embodiment 1 and anhydrous ethanol, and the embolism effect of the iopromide-ethanol injection of the present invention is slightly better than that of anhydrous ethanol in the incidence of complete embolism. The iopromide-ethanol injection of the present invention has a good vascular embolism effect and can meet the needs of clinical treatment of venous malformations. The iopromide-ethanol injection of embodiment 1 has a significantly lower degree of damage to surrounding tissues than anhydrous ethanol, and has lower side effects and higher treatment accuracy than anhydrous ethanol.

[0072] Experimental Example 3

[0073] 36 New Zealand rabbits were divided into nine groups, 4 in each group, and the right ear vein of each group of New Zealand rabbits was slowly injected with 1 mL of iopromide-ethanol injection obtained in Examples 1-4, Comparative Example A, Comparative Example B, Comparative Example C, Comparative Example D, and Comparative Example F, respectively. After the injection, the injection needle was pulled out, the injection site was marked, and each group of animals was developed in vivo under DSA, and the DSA development intensity value was recorded. Then observe for 14 days, and take ear tissue 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 was seen in the perivascular tissues, and the necrotic area was less than 1 / 3 of the tissue section, score 3; extensive necrosis of the perivascular tissues, and the necrotic area accounted for 1 / 3 or more of the tissue, score 4. The average values ​​of the vascular embolism degree and surrounding tissue damage degree scores of each group of animals were used as the venous occlusion pathology score and the surrounding tissue damage pathology score. Figure 3 The developing effect diagram of Example 1 and Comparative Example C. The experimental results of each group are shown in Table 7.

[0074] Table 7 Results of pathological scores of venous occlusion and surrounding tissue damage

[0075] Group Average DSA intensity Venous occlusion pathology score Pathological scoring of surrounding tissue damage Example 1 65127 1.50 0.75 Example 2 66287 1.50 0.75 Example 3 67300 1.75 1.25 Example 4 81744 1.00 0.50 Comparative Example A 61352 0.25 0.50 Comparative Example B 82354 0.25 0.75 Comparative Example C 35814 1.25 2.00 Comparative Example D 32919 0.75 1.50 Comparative Example F 31966 1.75 2.75

[0076] According to the attached Figure 3 As shown in the results of Table 7, the venous occlusion pathological scores of Comparative Examples A and B are less than 0.5, and the venous occlusion effect is poor. The pathological scores of surrounding tissue damage of Comparative Examples C, D, and F are greater than or equal to 1.5, and there is obvious surrounding tissue necrosis, and the side effects are obvious. In addition, the DSA development intensity of Comparative Examples C, D, and F is weak, and it is difficult to distinguish the blood vessel conditions with the naked eye.

[0077] The applicant has found through a large number of experiments that the iopromide-ethanol injection provided by the present invention has a good development effect when the ethanol concentration is 484mg / mL to 677mg / mL and the proportion of iopromide is 208mg / mL to 624mg / mL, the naked eye can distinguish the blood vessels in the body, the vascular embolization effect meets the clinical treatment effect, and the side effects and surrounding tissue damage are much less than anhydrous ethanol. The preferred composition of the present invention, that is, when the ethanol concentration is 630mg / mL to 677mg / mL, the iopromide concentration is 229mg / mL to 280mg / mL, and the injection water concentration is 35mg / mL to 110mg / mL, has a stronger vascular embolization effect, and the surrounding tissue damage is still much less than anhydrous ethanol, the degree of hyperplasia and necrosis is not significantly increased, and has a good in vitro and in vivo DSA development effect, a good vascular embolization treatment effect, and a higher treatment accuracy.

Claims

1. An iopromide-ethanol composition, characterized in that, The invention is an injection solution, which is composed of iopromide, ethanol and water for injection; wherein the concentration of iopromide is not less than 208 mg / ml, the concentration of ethanol is 480 mg / ml-680 mg / ml, and the concentration of water for injection is 30 mg / ml-150 mg / ml; in the iopromide, the content of E1 configuration is 8.0%-12.0%, the content of E2 configuration is 9.0%-14.0%, the content of Z1 configuration is 36%-40%, and the content of Z2 configuration is 38%-44%.

2. The iopromide-ethanol composition according to claim 1, characterized in that Iopromide completely dissolved in the liquid phase to form a true solution.

3. The iopromide-ethanol composition according to claim 1 or 2, characterized in that The concentration of iopromide is 208 mg / ml to 630 mg / ml, preferably 229 mg / ml to 280 mg / ml, and more preferably 229 mg / ml to 250 mg / ml.

4. The iopromide-ethanol composition according to claim 1 or 2, characterized in that The ethanol concentration is 630 mg / mL to 677 mg / mL, preferably 630 mg / mL to 657 mg / mL.

5. The iopromide-ethanol composition according to claim 1 or 2, characterized in that, The concentration of the water for injection is 33 mg / ml to 130 mg / ml, preferably 35 mg / ml to 125 mg / ml.

6. The iopromide-ethanol composition according to claim 1 or 2, characterized in that In the iopromide, the content of E1 configuration is 8.0%-10.0%, the content of E2 configuration is 9.0%-12.0%, the content of Z1 configuration is 38%-40%, and the content of Z2 configuration is 40-43%.

7. A method for preparing an iopromide-ethanol composition, characterized in that: Add the prescribed amount of iopromide to the prescribed amount of water for injection, heat until completely dissolved and keep warm. After the insulation is completed, cool the solution to below 50°C, add anhydrous ethanol, stir evenly, filter, and fill.

8. The preparation method according to claim 7, characterized in that: Heat to not less than 90°C and keep warm for 1-6 hours; preferably heat to 90°C to 100°C and keep warm for 2h to 4h.

9. Use of the iopromide-ethanol composition according to any one of claims 1 to 6 in the preparation of a pharmaceutical preparation, characterized in that: The pharmaceutical preparation is used for treating vascular malformation, lymphatic malformation or mixed malformation.

10. The use according to claim 9, characterized in that The drug preparation is used to treat venous malformations, arteriovenous malformations, abdominal cysts, liver cysts, kidney cysts, ovarian cysts or pelvic lymphocys; or to treat tumor interventional embolization and sclerosis, ablation of atrial fibrillation, ventricular septal ablation of hypertrophic obstructive cardiomyopathy or nerve destruction for intractable pain.

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