Iopamidol injection and a preparation method thereof

Abstract

The present application relates to the technical field of pharmaceutical preparation, in particular to a iopamidol injection and a preparation method thereof.The iopamidol injection comprises iopamidol, glycine, sodium citrate, a pH regulator and water for injection, and the pH regulator makes the pH value of the injection be 6.5-7.5.Compared with the prior art, the iopamidol injection of the present application has good stability, can withstand high-temperature sterilization, and avoids the use of aminotriol and calcium disodium edetate, and has good safety; compared with the same specification reference preparation, the iopamidol injection prepared by the present application has reduced viscosity, and improves the compliance of clinical application.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparation, in particular to a iopamidol injection and a preparation method thereof. BACKGROUND

[0002] Iopamidol injection is a non-ionic water-soluble iodine contrast agent, which has high iodine content, good imaging effect, low toxicity to blood vessel wall and nerve tissue, less adverse reactions, wide application range, and is mainly used for neuroradiology, angiography, urography, CT examination, arthrography, fistulography, digital subtraction angiography. Iopamidol injection was first developed by Bracco Company in Italy, and the product of iopamidol of Schering-Plough was listed in Germany in 1981, and the products of iopamidol of Schering AG Company and E Merck Company were listed in France and the United Kingdom in 1982, respectively, and then many pharmaceutical companies developed the product for clinical application.

[0003] Iopamidol injection exists in different raw material concentration specifications on the market. From the public ISOVUE instruction, it can be obtained that the auxiliary materials in iopamidol injection include tromethamine, calcium disodium edetate, hydrochloric acid and water for injection. From the clinical application, the injection has the following problems: (1) tromethamine in the auxiliary material as a pH buffer has side effects that cannot be ignored, which can cause hypoglycemia, hypotension, nausea, vomiting, and can inhibit respiration in severe cases, and can cause tissue necrosis and thrombophlebitis if leaked outside the blood vessel; (2) the viscosity of iopamidol injection is large, the irritability is strong during injection, and the patient's compliance is poor; (3) calcium disodium edetate as a metal ion chelating agent improves the stability of the injection, but there is a risk of complexing with calcium ions in the blood to reduce the concentration of blood calcium.

[0004] Therefore, it is still necessary to develop an iopamidol injection with good stability and high safety and a preparation method thereof. SUMMARY

[0005] In order to solve the above technical problems, the present application provides an iopamidol injection and a preparation method thereof, which solves the problems of side effects of tromethamine in iopamidol and large viscosity of the injection.

[0006] The technical scheme adopted by the present application is as follows:

[0007] An iopamidol injection, comprising iopamidol, glycine, sodium citrate, a pH adjusting agent and water for injection; the pH adjusting agent makes the pH value of the injection be 6.5-7.5.

[0008] Preferably, the pH adjusting agent is selected from one or more of citric acid, phosphoric acid, hydrochloric acid, acetic acid and tartaric acid.

[0009] Further preferably, the pH regulator is selected from citric acid, and the pH of the injection solution is adjusted to 6.8-7.2.

[0010] Preferably, the injection solution comprises 400-760 g iopamidol, 0.75-1.50 g glycine, 0.25-0.50 g sodium citrate, an appropriate amount of citric acid, and water for injection per 1000 mL of the injection solution, and the amount of citric acid is adjusted to make the pH of the injection solution 6.8-7.2.

[0011] Particularly preferably, the injection solution comprises 408 g iopamidol, 1.20 g glycine, 0.26 g sodium citrate, an appropriate amount of citric acid, and water for injection per 1000 mL of the injection solution, and the amount of citric acid is adjusted to make the pH of the injection solution 6.8-7.2.

[0012] Particularly preferably, the injection solution comprises 510 g iopamidol, 1.20 g glycine, 0.33 g sodium citrate, an appropriate amount of citric acid, and water for injection per 1000 mL of the injection solution, and the amount of citric acid is adjusted to make the pH of the injection solution 6.8-7.2.

[0013] Particularly preferably, the injection solution comprises 612 g iopamidol, 1.20 g glycine, 0.39 g sodium citrate, an appropriate amount of citric acid, and water for injection per 1000 mL of the injection solution, and the amount of citric acid is adjusted to make the pH of the injection solution 6.8-7.2.

[0014] Particularly preferably, the injection solution comprises 755 g iopamidol, 1.20 g glycine, 0.48 g sodium citrate, an appropriate amount of citric acid, and water for injection per 1000 mL of the injection solution, and the amount of citric acid is adjusted to make the pH of the injection solution 6.8-7.2.

[0015] The present application also provides a method for preparing the iopamidol injection solution as described above, and the preparation method specifically comprises the following steps:

[0016] Step 1: weigh the prescribed amount of 80-90% water for injection, add the prescribed amount of sodium citrate and glycine, stir and dissolve to obtain solution 1;

[0017] Step 2: warm solution 1 to 75-80°C, add the prescribed amount of iopamidol, stir and dissolve completely, and then cool the solution to room temperature, and adjust the pH of the solution to 6.5-7.5 with a pH regulator to obtain solution 2;

[0018] Step 3: add the remaining prescribed amount of water for injection to solution 2, make up the volume, filter through a microporous membrane, and fill;

[0019] Step 4: sterilize and package.

[0020] Preferably, the pH regulator in step 1 is selected from citric acid, and the pH of the injection solution is adjusted to 6.8-7.2.

[0021] Preferably, the water for injection in step 1 is 90% of the prescribed amount of water for injection.

[0022] Preferably, the sterilization in step 4 is performed at 121℃ for 15 minutes.

[0023] The iopamidol injection of the present application can be used for the medical use in the preparation of X-ray contrast agents, which can be used for lumbar, chest, cervical spinal cord, cerebral vascular angiography, peripheral arterial and venous angiography, vascular angiography, coronary angiography, urinary tract and joint angiography, CT enhancement examination.

[0024] Compared with the prior art, the technical scheme of the present application has the following beneficial technical effects: (1) the iopamidol injection of the present application has good stability, can withstand high-temperature sterilization, and avoids the use of aminotriol and calcium edetate, thereby improving the safety of the injection; (2) compared with the same specification reference preparation, the iopamidol injection prepared by the present application has reduced viscosity, thereby improving the compliance of the patient in clinical use. DETAILED DESCRIPTION

[0025] In order to better understand the technical scheme of the present application, the technical scheme of the present application will be further described below in combination with specific examples, which are only used to help understand the present application and should not be regarded as a specific limitation on the present application.

[0026] Example 1

[0027] Prescription (based on 1000mL): iopamidol 408g, glycine 1.20g, sodium citrate 0.26g, and appropriate amount of citric acid.

[0028] Preparation method: add 90% of the total water amount of the prescription in the liquid preparation tank, add the prescription amount of sodium citrate and glycine, and stir to dissolve; heat the solution to 75-80℃, add the prescription amount of iopamidol, stir to dissolve completely and mix uniformly, cool the solution to room temperature, add citric acid to adjust the pH of the solution to 6.8-7.2, and add the remaining prescription amount of water for injection to constant volume; filter the liquid medicine through a 0.22μm sterilization filter, fill, and finally sterilize at 121℃ for 15 minutes.

[0029] Example 2

[0030] Prescription (based on 1000mL): iopamidol 510g, glycine 1.20g, sodium citrate 0.33g, and appropriate amount of citric acid.

[0031] Preparation method: in the liquid preparation tank, add 90% of the total water amount of injection water, add the prescription amount of sodium citrate and glycine, stir and dissolve; the solution is heated to 75-80℃, the prescription amount of iopamidol is added, stirred and dissolved completely, mixed evenly, the solution is cooled to room temperature, then citric acid is added to adjust the solution pH value to 6.8-7.2, and the remaining prescription amount of injection water is added to constant volume; the liquid is filtered through a 0.22μm sterilization filter, filled, and finally sterilized at 121℃ for 15min.

[0032] Example 3

[0033] Prescription (per 1000mL): iopamidol 612g, glycine 1.20g, sodium citrate 0.39g, and citric acid as appropriate.

[0034] Preparation method: in the liquid preparation tank, add 90% of the total water amount of injection water, add the prescription amount of sodium citrate and glycine, stir and dissolve; the solution is heated to 75-80℃, the prescription amount of iopamidol is added, stirred and dissolved completely, mixed evenly, the solution is cooled to room temperature, then citric acid is added to adjust the solution pH value to 6.8-7.2, and the remaining prescription amount of injection water is added to constant volume; the liquid is filtered through a 0.22μm sterilization filter, filled, and finally sterilized at 121℃ for 15min.

[0035] Example 4

[0036] Prescription (per 1000mL): iopamidol 755g, glycine 1.20g, sodium citrate 0.48g, and citric acid as appropriate.

[0037] Preparation method: in the liquid preparation tank, add 90% of the total water amount of injection water, add the prescription amount of sodium citrate and glycine, stir and dissolve; the solution is heated to 75-80℃, the prescription amount of iopamidol is added, stirred and dissolved completely, mixed evenly, the solution is cooled to room temperature, then citric acid is added to adjust the solution pH value to 6.8-7.2, and the remaining prescription amount of injection water is added to constant volume; the liquid is filtered through a 0.22μm sterilization filter, filled, and finally sterilized at 121℃ for 15min.

[0038] Example 5

[0039] Prescription (per 1000mL): iopamidol 755g, glycine 0.75g, sodium citrate 0.48g, and citric acid as appropriate.

[0040] Preparation method: in the liquid preparation tank, add 90% of the total water amount of injection water, add the prescription amount of sodium citrate and glycine, stir and dissolve; the solution is heated to 75-80°C, the prescription amount of iopamidol is added, stirred and dissolved completely, mixed evenly, the solution is cooled to room temperature, the pH value of the solution is adjusted to 6.8-7.2 by adding citric acid, and the remaining prescription amount of injection water is added to constant volume; the liquid is filtered through a 0.22 μm sterilization filter, filled, and finally sterilized at 121°C for 15 min.

[0041] Example 6

[0042] Prescription (per 1000 mL): iopamidol 755 g, glycine 1.50 g, sodium citrate 0.48 g, and citric acid as needed.

[0043] Preparation method: in the liquid preparation tank, add 90% of the total water amount of injection water, add the prescription amount of sodium citrate and glycine, stir and dissolve; the solution is heated to 75-80°C, the prescription amount of iopamidol is added, stirred and dissolved completely, mixed evenly, the solution is cooled to room temperature, the pH value of the solution is adjusted to 6.8-7.2 by adding citric acid, and the remaining prescription amount of injection water is added to constant volume; the liquid is filtered through a 0.22 μm sterilization filter, filled, and finally sterilized at 121°C for 15 min.

[0044] Comparative Example 1

[0045] Prescription (per 1000 mL): iopamidol 408 g, glycine 1.20 g, sodium tartrate 0.26 g, and citric acid as needed.

[0046] Preparation method: in the liquid preparation tank, add 90% of the total water amount of injection water, add the prescription amount of sodium tartrate and glycine, stir and dissolve; the solution is heated to 75-80°C, the prescription amount of iopamidol is added, stirred and dissolved completely, mixed evenly, the solution is cooled to room temperature, the pH value of the solution is adjusted to 6.8-7.2 by adding citric acid, and the remaining prescription amount of injection water is added to constant volume; the liquid is filtered through a 0.22 μm sterilization filter, filled, and finally sterilized at 121°C for 15 min.

[0047] Comparative Example 2

[0048] Prescription (per 1000 mL): iopamidol 408 g, glycine 1.20 g, sodium citrate 0.26 g, and hydrochloric acid as needed.

[0049] Preparation method: in the liquid preparation tank, add 90% of the total water amount of injection water, add the prescribed amount of sodium citrate and glycine, stir and dissolve; heat the solution to 75-80°C, add the prescribed amount of iopamidol, stir and dissolve completely, mix evenly, cool the solution to room temperature, then add hydrochloric acid to adjust the pH of the solution to 6.8-7.2, add the remaining prescribed amount of injection water to constant volume; filter the liquid medicine through a 0.22 μm sterilization filter, fill, and finally sterilize at 121°C for 15 min.

[0050] Comparative Example 3

[0051] Prescription (per 1000 mL): Iopamidol 408 g, histidine 1.20 g, sodium citrate 0.26 g, and citric acid as needed.

[0052] Preparation method: in the liquid preparation tank, add 90% of the total water amount of injection water, add the prescribed amount of sodium citrate and glycine, stir and dissolve; heat the solution to 75-80°C, add the prescribed amount of iopamidol, stir and dissolve completely, mix evenly, cool the solution to room temperature, then add citric acid to adjust the pH of the solution to 6.8-7.2, add the remaining prescribed amount of injection water to constant volume; filter the liquid medicine through a 0.22 μm sterilization filter, fill, and finally sterilize at 121°C for 15 min.

[0053] Comparative Example 4

[0054] This example is ISOVUE purchased on the market, with a specification of 200 mg I / m1.

[0055] Comparative Example 5

[0056] This example is ISOVUE purchased on the market, with a specification of 250 mg I / m1.

[0057] Comparative Example 6

[0058] This example is ISOVUE purchased on the market, with a specification of 300 mg I / m1.

[0059] Comparative Example 7

[0060] Prescription (per 1000 mL): Iopamidol 755 g, glycine 1.20 g, sodium tartrate 0.48 g, and citric acid as needed.

[0061] Preparation method: in the liquid preparation tank, add 90% of the total water amount of injection water, add the prescribed amount of sodium tartrate and glycine, stir and dissolve; heat the solution to 75-80°C, add the prescribed amount of iopamidol, stir and dissolve completely, mix evenly, cool the solution to room temperature, then add citric acid to adjust the pH of the solution to 6.8-7.2, add the remaining prescribed amount of injection water to constant volume; filter the liquid medicine through a 0.22 μm sterilization filter, fill, and finally sterilize at 121°C for 15 min.

[0062] Comparative Example 8

[0063] Prescription (per 1000 mL): Iopamidol 755 g, glycine 1.20 g, sodium citrate 0.48 g, hydrochloric acid as appropriate.

[0064] Preparation method: injectable water of 90% of the total water amount in the prescription was added to a liquid preparation tank, the prescription amount of sodium citrate and glycine was added and dissolved by stirring; the solution was warmed to 75-80°C, the prescription amount of iopamidol was added, and the solution was completely dissolved and mixed by stirring; after the solution was cooled to room temperature, hydrochloric acid was added to adjust the pH of the solution to 6.8-7.2, and the remaining prescription amount of injectable water was added to make up the volume; the solution was filtered through a 0.22 μm sterilizing filter, filled, and finally sterilized at 121°C for 15 min.

[0065] Comparative Example 9

[0066] Prescription (per 1000 mL): Iopamidol 755 g, histidine 1.20 g, sodium citrate 0.48 g, citric acid as appropriate.

[0067] Preparation method: injectable water of 90% of the total water amount in the prescription was added to a liquid preparation tank, the prescription amount of sodium citrate and histidine was added and dissolved by stirring; the solution was warmed to 75-80°C, the prescription amount of iopamidol was added, and the solution was completely dissolved and mixed by stirring; after the solution was cooled to room temperature, citric acid was added to adjust the pH of the solution to 6.8-7.2, and the remaining prescription amount of injectable water was added to make up the volume; the solution was filtered through a 0.22 μm sterilizing filter, filled, and finally sterilized at 121°C for 15 min.

[0068] Comparative Example 10

[0069] Prescription (per 1000 mL): Iopamidol 755 g, glycine 0.70 g, sodium citrate 0.48 g, citric acid as appropriate.

[0070] Preparation method: injectable water of 90% of the total water amount in the prescription was added to a liquid preparation tank, the prescription amount of sodium citrate and glycine was added and dissolved by stirring; the solution was warmed to 75-80°C, the prescription amount of iopamidol was added, and the solution was completely dissolved and mixed by stirring; after the solution was cooled to room temperature, citric acid was added to adjust the pH of the solution to 6.8-7.2, and the remaining prescription amount of injectable water was added to make up the volume; the solution was filtered through a 0.22 μm sterilizing filter, filled, and finally sterilized at 121°C for 15 min.

[0071] Comparative Example 11

[0072] Prescription (per 1000 mL): Iopamidol 755 g, glycine 1.20 g, sodium citrate 0.20 g, citric acid as appropriate.

[0073] Preparation method: in the liquid preparation tank, add 90% of the total water amount of injection, add the prescribed amount of sodium citrate and glycine, stir and dissolve; heat the solution to 75-80℃, add the prescribed amount of iopamidol, stir and dissolve completely, mix evenly, cool the solution to room temperature, add citric acid to adjust the pH value of the solution to 6.8-7.2, and add the remaining injection water to constant volume; the liquid is filtered through a 0.22 μm sterilization filter, filled, and finally sterilized at 121℃ for 15 min.

[0074] Comparative Example 12

[0075] This example is ISOVUE purchased on the market, with a specification of 370 mg I / m1.

[0076] Product quality detection method:

[0077] 1. The content detection method of the iopamidol injection described in the application: refer to the Chinese Pharmacopoeia 2020 edition, high performance liquid chromatography (general rule 0512) for determination;

[0078] Test solution: accurately measure an appropriate amount of the product, dilute with water to prepare a solution containing about 0.2 mg of iopamidol per 1 mL;

[0079] Reference solution: take an appropriate amount of iopamidol reference, accurately weigh and add water to dissolve and dilute to prepare a solution containing about 0.2 mg per 1 mL.

[0080] Chromatographic conditions: use octadecylsilane bonded silica gel as the filler, water as the mobile phase A, methanol-water (25:75) as the mobile phase B, perform gradient elution according to the following table; the detection wavelength is 240 nm; the injection volume is 20 μL.

[0081]

[0082] 2. The pH detection method of the iopamidol injection described in the application: refer to the Chinese Pharmacopoeia 2020 edition, pH value determination method (general rule 0631) for determination.

[0083] 3. The detection method of inorganic iodide of the iopamidol injection described in the application: accurately measure 20 mL of the product, add 20-30 mL of acetic acid-sodium acetate buffer (pH 4.66) (Merck, 1.07827.1000), and immediately titrate with silver nitrate titration solution (0.001 mol / L) by potential titration method (general rule 0701). Each 1 mL of silver nitrate titration solution (0.001 mol / ) corresponds to 126.9 μg of I. The content of inorganic iodide as iodine (I) in the product per 100 mL should not exceed 4.0 mg.

[0084] 4. The iopamidol injection solution according to the present application, wherein the method for detecting the related substances of the iopamidol injection solution is as follows: a chromatographic column: ZORBAX SB-phenyl (250 mm x 4.6 mm, 5 μm) (two chromatographic columns connected in series); a mobile phase A: water, a mobile phase B: acetonitrile-water (50:50), gradient elution is performed according to the following table; a detection wavelength: 240 nm; a flow rate: 2.0 mL / min; a column temperature: 60°C; a sample injection volume: 20 μL.

[0085]

[0086] Test 1

[0087] The iopamidol injection solution sample is sent for inspection before and after sterilization, and the changes in the pH value, inorganic iodide and iopamidol content before and after the sample is sent for inspection are investigated, and the detection results are shown in Table 1.

[0088] Table 1

[0089]

[0090] According to the results in Table 1, it can be seen that the iopamidol injection solutions prepared in Examples 1-6 do not have significant changes in properties after high-temperature sterilization, and have good stability, that is, the iopamidol injection solution according to the present application is resistant to terminal sterilization, while the iopamidol injection solutions prepared in Comparative Examples 1-3 and 7-11 have a significant increase in inorganic iodide after high-temperature sterilization, and are not resistant to terminal sterilization.

[0091] Test 2

[0092] The sample is placed at a high temperature of 60°C±2°C for 30 days, samples are taken at the beginning of storage (0 days), 10 days and the end (30 days), respectively, and the pH, inorganic iodide, total impurity amount and iopamidol content of the sample are determined and compared, and the stability of the sample is analyzed, and the results are shown in Table 2.

[0093] Table 2

[0094]

[0095]

[0096] According to the results in Table 2, it can be seen that the iopamidol injection solutions prepared in Examples 1-6 do not have significant changes in properties after being placed at 60°C for 30 days, can maintain the long-term stability of the drug solution, and the stability of the iopamidol injection solutions prepared in Examples 1-6 has no significant difference from the stability of Comparative Examples 4, 5, 6 and 12.

[0097] Test 3

[0098] The injection prepared in Examples 1-6 and the injection prepared in Comparative Examples 4, 5, 6 and 12 were heated to different temperatures, and the viscosity (viscosity unit: mPa.S) was determined by using a Brookfield DV3T rotary viscometer. The results are shown in Table 3.

[0099] Table 3

[0100]

[0101] As can be seen from the results in Table 3, the viscosity of the iopamidol injection of the present application is less than that of the reference preparation, and the compliance of the patient in clinical use can be improved.

[0102] The above examples are only used to illustrate the technical solutions of the present application, and are not intended to limit the present application; although the present application has been described in detail with reference to the foregoing examples, those skilled in the art should understand that the technical solutions recorded in the foregoing examples can still be modified, or some of the technical features can be replaced by equivalents; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present application.

Claims

1. An iopamidol injection solution, characterized in that, Each 1000mL injection solution contains 400-760g of iopamidol, 0.75-1.50g of glycine, 0.25-0.50g of sodium citrate, an appropriate amount of citric acid, and water for injection; the amount of citric acid is such that the pH of the injection solution is adjusted to 6.8-7.

2.

2. The injection solution according to claim 1, characterized in that, Each 1000mL injection solution contains 408g of iopamidol, 1.20g of glycine, 0.26g of sodium citrate, an appropriate amount of citric acid, and water for injection; the amount of citric acid is adjusted to adjust the pH of the injection solution to 6.8-7.

2.

3. The injection solution according to claim 1, characterized in that, Each 1000mL injection solution contains 510g of iopamidol, 1.20g of glycine, 0.33g of sodium citrate, an appropriate amount of citric acid, and water for injection; the amount of citric acid is adjusted to adjust the pH of the injection solution to 6.8-7.

2.

4. The injection solution according to claim 1, characterized in that, Each 1000mL injection solution contains 612g of iopamidol, 1.20g of glycine, 0.39g of sodium citrate, an appropriate amount of citric acid, and water for injection; the amount of citric acid is adjusted to adjust the pH of the injection solution to 6.8-7.

2.

5. The injection solution according to claim 1, characterized in that, Each 1000mL injection solution contains 755g of iopamidol, 1.20g of glycine, 0.48g of sodium citrate, an appropriate amount of citric acid, and water for injection; the amount of citric acid is adjusted to adjust the pH of the injection solution to 6.8-7.

2.

6. A method for preparing the injection solution as described in claim 1, characterized in that, Includes the following steps: Step 1: Weigh 80-90% of the prescribed amount of water for injection, add the prescribed amount of sodium citrate and glycine, stir to dissolve, and obtain solution 1; Step 2: Heat solution 1 to 75-80℃, add the prescribed amount of iopamidol, stir until completely dissolved, cool the solution to room temperature, and adjust the pH of the solution to 6.8-7.2 with citric acid to obtain solution 2; Step 3: Add the remaining prescribed amount of water for injection to solution 2 to make up the volume, filter through a microporous membrane, and fill the solution; Step 4: Sterilize and package.

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