A gadobutrol injection and its preparation method

Abstract

The present invention provides a gadobutrol injection and a preparation method thereof, belonging to the technical field of contrast agents. The preparation method of the gadobutrol injection provided by the present invention comprises the following steps: (1) mixing a pH regulator with a part of water to obtain a first solution; (2) mixing the first solution with trometamol, cobutriol calcium, gadobutrol and the remaining water to obtain the gadobutrol injection; the mixing temperature in the steps (1)-(2) is ≤50°C. By changing the pH adjustment sequence, the present invention avoids local over-acidification during the final adjustment; at the same time, trometamol is used as a pH buffer, which has a stronger buffering capacity compared with phosphates; cobutriol calcium is used as a metal ion chelating agent in combination, and has a stronger chelating ability for free gadolinium ions compared with cobutriol calcium sodium, thereby reducing the content of free gadolinium ions in the gadobutrol injection.

Description

Technical Field

[0001] The present invention belongs to the technical field of contrast agents, and particularly relates to a gadobutrol injection and a preparation method thereof. Background Art

[0002] Gadobutrol injection (1.0 mol / L) is a gadolinium chelate injection with gadobutrol as the active ingredient, developed by Bayer in Germany, and is usually used as a contrast agent for magnetic resonance imaging (MRI). Gadobutrol has a cyclic structure with high chelation stability and a low release risk. The European Society of Urogenital Radiology (ESUR) classifies it as a gadolinium-based contrast agent with a low risk of NSF (Nephrogenic Systemic Fibrosis) in the NSF risk classification.

[0003] Chinese Patent CN106620726B proposes a preparation method of gadobutrol injection. Specifically, phosphate is mixed with a part of water to obtain a mixed solution A; calcium cobutate sodium, gadobutrol and the mixed solution A are mixed evenly to obtain a mixed solution B; the mixed solution B is diluted with the remaining part of water to obtain gadobutrol injection. At the same time, this patent discloses that the pH value of the gadobutrol injection is 6.7 - 8.0. If the pH value of the diluted mixed solution is higher than the above range, the pH value can be further adjusted with an acid after dilution. However, the content of free gadolinium ions in the gadobutrol injection prepared by the method of this patent is ≥ 0.008 mg / mL, and the content of free gadolinium ions is relatively high. Summary of the Invention

[0004] The purpose of the present invention is to provide a gadobutrol injection and a preparation method thereof, which overcome the technical defect that the content of free gadolinium ions in the gadobutrol injection prepared by the prior art is relatively high.

[0005] In order to achieve the purpose of the present invention, the present invention provides the following technical solutions:

[0006] A preparation method of gadobutrol injection, comprising the following steps:

[0007] (1) Mix a pH regulator with a part of water to obtain a first solution;

[0008] (2) Mix the first solution with tromethamine, calcium cobutate, gadobutrol and the remaining water to obtain gadobutrol injection;

[0009] The mixing temperature in the steps (1) - (2) is ≤ 50 °C.

[0010] Preferably, based on the volume of the gadobutrol injection as the unit volume, the concentration of gadobutrol is 0.59 - 0.66 g / mL, the concentration of cobutamol calcium is 0.46 - 0.52 mg / mL, the concentration of trometamol is 1.15 - 1.28 mg / mL, and the volume fraction of the pH regulator is 0.6%.

[0011] Preferably, the pH regulator is hydrochloric acid, and the concentration of the pH regulator is 1.0 mol / L.

[0012] Preferably, the independent temperature for mixing in the steps (1)-(2) is 20 - 50 °C.

[0013] Preferably, the mixing in the step (2) includes: mixing trometamol with the first solution to obtain a second solution; mixing cobutamol calcium with the second solution to obtain a third solution; mixing gadobutrol with the third solution and the remaining water to obtain the gadobutrol injection.

[0014] Preferably, the dosage ratio of the partial water to the remaining water is 2 - 3:3 - 2.

[0015] Preferably, after mixing in the step (2), filtration and sterilization are sequentially carried out.

[0016] Preferably, the sterilization is moist heat sterilization, the temperature of the sterilization is 121 °C, and the sterilization time is 15 min.

[0017] The present invention also provides a gadobutrol injection prepared by the preparation method described in the above technical solution, and the content of free gadolinium ions in the gadobutrol injection < 0.0002 mg / mL.

[0018] Preferably, the content of heavy metal ions other than free gadolinium ions in the gadobutrol injection ≤ 19 ppm.

[0019] The present invention provides a preparation method of gadobutrol injection, comprising the following steps: (1) Mixing a pH regulator with a part of water to obtain a first solution; (2) Mixing the first solution with trometamol, cobtrol calcium, gadobutrol and the remaining water to obtain gadobutrol injection; the mixing temperature in the steps (1)-(2) is ≤ 50°C. By first mixing the pH regulator evenly with a part of water, the present invention changes the pH adjustment sequence in the traditional method, avoids local over-acidity of the gadobutrol injection during the final adjustment, thereby preventing the situation of gadolinium dissociation, and greatly reducing the content of free gadolinium ions in the gadobutrol injection; at the same time, trometamol is used as a pH buffer, and its effective pH regulation range is usually between 7.0 and 9.2, which has a stronger buffering capacity than phosphate, and can better control the pH adjustment range during the preparation of gadobutrol injection, making the gadobutrol injection have better stability, which is beneficial to reducing the content of free gadolinium ions in the gadobutrol injection. In addition, it can avoid the problem that phosphate is likely to form precipitates with heavy metal ions (such as gadolinium ions and other heavy metal ions brought in by production components and raw materials during the production process); the combined use of cobtrol calcium as a metal ion chelating agent has a stronger chelating ability for free gadolinium ions than cobtrol calcium sodium, thereby being able to reduce the content of free gadolinium ions in the gadobutrol injection. The results of the examples show that the content of free gadolinium ions in the gadobutrol injection prepared by the preparation method of the present invention is < 0.0002 mg / mL. Further, the preparation method of the gadobutrol injection provided by the present invention has a simple process, easily available raw materials, and low cost. Detailed Description of the Invention

[0020] The present invention provides a preparation method of gadobutrol injection, comprising the following steps:

[0021] (1) Mixing a pH regulator with a part of water to obtain a first solution;

[0022] (2) Mixing the first solution with trometamol, cobtrol calcium, gadobutrol and the remaining water to obtain gadobutrol injection;

[0023] The mixing temperature in the steps (1)-(2) is ≤ 50°C.

[0024] In the present invention, unless otherwise specified, all the preparation raw materials used are commercially available products well-known to those skilled in the art.

[0025] First, the preparation raw materials of the gadobutrol injection according to the present invention are described. The preparation raw materials of the gadobutrol injection according to the present invention include a pH regulator, trometamol, gadobutrol and water.

[0026] In the present invention, the pH regulator is preferably hydrochloric acid, and the concentration of the pH regulator is preferably 1.0 mol / L; based on the volume of the gadobutrol injection as the unit volume, the volume fraction of the pH regulator is preferably 0.6%.

[0027] In the present invention, based on the volume of the gadobutrol injection as the unit volume, the concentration of trometamol is preferably 1.15 - 1.28 mg / mL, more preferably 1.18 - 1.25 mg / mL, and further preferably 1.21 - 1.22 mg / mL. In the present invention, trometamol is used as a pH buffer. The effective range for trometamol to regulate the pH value is generally between 7.0 and 9.2, and it has a stronger buffering capacity than phosphate, enabling better control of the pH adjustment range during the preparation of gadobutrol injection; in addition, using trometamol as a pH buffer can avoid the problem that phosphate easily causes precipitation of heavy metal ions (such as gadolinium ions and other heavy metal ions introduced by production components and raw materials during the production process).

[0028] In the present invention, based on the volume of the gadobutrol injection as the unit volume, the concentration of cobutri-calcium is preferably 0.46 - 0.52 mg / mL, more preferably 0.48 - 0.51 mg / mL, and further preferably 0.49 - 0.50 mg / mL. In the present invention, cobutri-calcium is used as a metal ion chelating agent, and it has a stronger chelating ability for free gadolinium ions than cobutri-calcium sodium, which is beneficial to reducing the content of free gadolinium ions in the gadobutrol injection.

[0029] In the present invention, the gadobutrol is preferably gadobutrol hydrate, and more preferably gadobutrol monohydrate; in the present invention, based on the volume of the gadobutrol injection as the unit volume, the concentration of gadobutrol is preferably 0.59 - 0.66 g / mL, more preferably 0.61 - 0.64 g / mL, and further preferably 0.62 - 0.63 g / mL.

[0030] In the present invention, the water is preferably water for injection; in the examples of the present invention, freshly prepared water for injection is specifically used, and the freshly prepared water for injection is specifically the newly unsealed water for injection. In the present invention, the water is used in two parts, that is, first, part of the water is mixed with the pH regulator, which avoids local over-acidity of the gadobutrol injection during the final adjustment, thereby preventing the situation of gadolinium dissociation, greatly reducing the content of free gadolinium ions in the gadobutrol injection, and finally, the remaining water is used to make up the required volume. In the present invention, the dosage ratio of the part of water to the remaining water is preferably 2 - 3:3 - 2, and further preferably 1:1.

[0031] The preparation method of the gadobutrol injection according to the present invention will be described below.

[0032] The present invention mixes a pH regulator with a part of water to obtain a first solution. In the present invention, the temperature of the mixing is ≤50°C, preferably 20 - 50°C, specifically it can be 20 - 30°C, 30 - 40°C or 40 - 50°C. In the present invention, the mixing method is preferably stirring and mixing. The present invention has no special limitation on the stirring conditions of the stirring and mixing, as long as the purpose of uniform mixing can be achieved.

[0033] After obtaining the first solution, the present invention mixes the first solution with tromethamine, calcium cobutate, gadobutrol and the remaining water to obtain a gadobutrol injection. In the present invention, the mixing preferably includes: mixing tromethamine with the first solution to obtain a second solution; mixing calcium cobutate with the second solution to obtain a third solution; mixing gadobutrol with the third solution and the remaining water to obtain a gadobutrol injection. In the present invention, the temperature of the mixing of tromethamine and the first solution is ≤50°C, preferably 20 - 50°C, specifically it can be 20 - 30°C, 30 - 40°C or 40 - 50°C; the mixing method is preferably stirring and mixing. In the present invention, by controlling the mixing temperature within the above range, on the basis of making the raw materials easy to dissolve, the situation that the raw materials are unstable and easy to decompose under high temperature conditions can be avoided. The present invention adds tromethamine after obtaining the first mixed solution. Tromethamine can neutralize the acidity brought by hydrochloric acid, avoiding the situation that gadobutrol will release gadolinium ions when encountering acid, which is beneficial to further reducing the content of free gadolinium ions in the gadobutrol injection.

[0034] After obtaining the second solution, the present invention preferably mixes calcium cobutate with the second solution to obtain a third solution. In the present invention, the temperature of the mixing of calcium cobutate and the second solution is ≤50°C, preferably 20 - 50°C, specifically it can be 20 - 30°C, 30 - 40°C or 40 - 50°C; the mixing method is preferably stirring and mixing. In the present invention, by controlling the mixing temperature within the above range, on the basis of making the raw materials easy to dissolve, the situation that the raw materials are unstable and easy to decompose under high temperature conditions can be avoided. The present invention adds calcium cobutate after obtaining the second mixed solution. Calcium cobutate, as a complexing agent, can complex the gadolinium ions attached to the subsequently added gadobutrol in the first time, which is beneficial to further reducing the content of free gadolinium ions in the gadobutrol injection.

[0035] After obtaining the third solution, the present invention preferably mixes gadobutrol with the third solution and the remaining water to obtain a gadobutrol injection. In the present invention, the temperature of the mixing of gadobutrol with the third solution and the remaining water is ≤50°C, preferably 20 - 50°C, specifically it can be 20 - 30°C, 30 - 40°C or 40 - 50°C; the mixing method is preferably stirring and mixing. In the present invention, by controlling the mixing temperature within the above range, on the basis of making the raw materials easy to dissolve, the situation that the raw materials are unstable and easy to decompose under high temperature conditions can be avoided.

[0036] In the present invention, after mixing gadobutrol with the third solution and the remaining water, it is preferably further followed by filtration and sterilization in sequence. In the present invention, the filter membrane used for filtration is preferably a polyethersulfone (PES) filter membrane, and the pore size of the filter membrane is preferably 0.22 μm; the present invention has no special limitation on the specific operation method of the filtration, and the conventional filtration method in the art can be adopted. In the present invention, the sterilization is preferably moist heat sterilization, the temperature of the moist heat sterilization is preferably 121 °C, and the time of the moist heat sterilization is preferably 15 min.

[0037] The present invention also provides a gadobutrol injection prepared by the preparation method described in the above technical solution. The content of free gadolinium ions in the gadobutrol injection is < 0.0002 mg / mL, and more preferably 0.00002 - 0.00012 mg / mL.

[0038] In the present invention, the pH value of the gadobutrol injection is preferably 7.0 - 8.0, and more preferably 7.3 - 7.5.

[0039] In the present invention, the content of heavy metal ions other than free gadolinium ions in the gadobutrol injection is preferably ≤ 19 ppm, and specifically can be 15 - 19 ppm.

[0040] In the present invention, the content of gadobutrol in the gadobutrol injection is preferably 96.34 - 103.21%.

[0041] In the present invention, the content of cobutamol calcium in the gadobutrol injection is preferably 0.35 - 0.62 mg / mL.

[0042] In the present invention, the content of butrol (denoted as impurity B) in the gadobutrol injection is ≤ 0.04%, specifically 0.01 - 0.04%; 4,10-bis(2,3-dihydroxy-1-hydroxymethylpropyl)-1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (Di-TOBO, denoted as impurity A) and the complex of 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and gadolinium (Gd-D03A, denoted as impurity C) are not detected in the gadobutrol injection.

[0043] In the present invention, the specification of the gadobutrol injection is preferably 7.5 mL. At this time, the preparation raw materials preferably include 4.45 - 4.90 g of gadobutrol monohydrate, 3.50 - 3.86 mg of cobutamol calcium, 8.65 - 9.55 mg of trometamol, 45 μL of hydrochloric acid (1 mol / L), and water based on the volume of the gadobutrol injection being 7.5 mL.

[0044] To further illustrate the present invention, a gadobutrol injection and its preparation method provided by the present invention will be described in detail below in conjunction with embodiments, but they should not be construed as limiting the scope of protection of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts belong to the scope of protection of the present invention.

[0045] Example 1

[0046] (1) Add 300 mL of fresh injection water to the preparation equipment, add 4500 μL of hydrochloric acid with a concentration of 1.0 mol / L, control the temperature at 20 - 30 °C, and mix evenly to obtain the first solution;

[0047] (2) Add 865 mg of trometamol to the first solution, control the temperature at 20 - 30 °C, and mix evenly to obtain the second solution;

[0048] (3) Add 350 mg of cobutamol calcium to the second solution, control the temperature at 20 - 30 °C, and mix evenly to obtain the third solution;

[0049] (4) Add 445 g of gadobutrol monohydrate to the third solution, control the temperature at 20 - 30 °C, and mix evenly to obtain a mixed solution; use the remaining injection water to make the volume of the above mixed solution up to 750 mL, filter it with a 0.22 μm PES filter membrane, and sterilize it by moist heat at 121 °C for 15 min to obtain the gadobutrol injection.

[0050] Example 2

[0051] (1) Add 450 mL of fresh injection water to the preparation equipment, add 4500 μL of hydrochloric acid with a concentration of 1.0 mol / L, control the temperature at 40 - 50 °C, and mix evenly to obtain the first solution;

[0052] (2) Add 955 mg of trometamol to the first solution, control the temperature at 40 - 50 °C, and mix evenly to obtain the second solution;

[0053] (3) Add 386 mg of cobutamol calcium to the second solution, control the temperature at 40 - 50 °C, and mix evenly to obtain the third solution;

[0054] (4) Add 490 g of gadobutrol monohydrate to the third solution, control the temperature at 40 - 50 °C, and mix evenly to obtain a mixed solution; use the remaining injection water to make the volume of the above mixed solution up to 750 mL, filter it with a 0.22 μm PES filter membrane, and sterilize it by moist heat at 121 °C for 15 min to obtain the gadobutrol injection.

[0055] Example 3

[0056] (1) Add 375 mL of fresh injection water to the preparation equipment, add 4500 μL of hydrochloric acid with a concentration of 1.0 mol / L, control the temperature at 30 - 40 °C, and mix evenly to obtain the first solution;

[0057] (2) Add 910 mg of trometamol to the first solution, control the temperature at 30 - 40 °C, and mix evenly to obtain the second solution;

[0058] (3) Add 368 mg of cobutamol calcium to the second solution, control the temperature at 30 - 40 °C, and mix evenly to obtain the third solution;

[0059] (4) Add 467.5 g of gadobutrol monohydrate to the third solution, control the temperature at 30 - 40 °C, and mix evenly to obtain the mixed solution; make up the volume of the above mixed solution to 750 mL with the remaining injection water, filter it with a 0.22 - μm PES filter membrane, and sterilize it by moist heat at 121 °C for 15 min to obtain the gadobutrol injection.

[0060] Comparative Example 1

[0061] (1) Add 375 mL of fresh injection water to the preparation equipment, add 4500 μL of hydrochloric acid with a concentration of 1.0 mol / L, control the temperature at 70 - 80 °C, and mix evenly to obtain the first solution;

[0062] (2) Add 910 mg of trometamol to the first solution, control the temperature at 70 - 80 °C, and mix evenly to obtain the second solution;

[0063] (3) Add 385 mg of cobutamol calcium to the second solution, control the temperature at 70 - 80 °C, and mix evenly to obtain the third solution;

[0064] (4) Add 467.5 g of gadobutrol monohydrate to the third solution, control the temperature at 70 - 80 °C, and mix evenly to obtain the mixed solution; make up the volume of the above mixed solution to 750 mL with the remaining injection water, filter it with a 0.22 - μm PES filter membrane, and sterilize it by moist heat at 121 °C for 15 min to obtain the gadobutrol injection.

[0065] Comparative Example 2

[0066] (1) Add 375 mL of fresh injection water to the preparation equipment, then add 910 mg of trometamol, control the temperature at 30 - 40 °C, and mix evenly to obtain the first solution;

[0067] (2) Add 385 mg of cobutamol calcium to the first solution, control the temperature at 30 - 40 °C, and mix evenly to obtain the second solution;

[0068] (3) Add 467.5 g of gadobutrol monohydrate to the second solution, control the temperature at 30 - 40 °C, and mix evenly to obtain the third solution;

[0069] (4) Add 4500 μL of hydrochloric acid with a concentration of 1.0 mol / L to the third solution, make up the volume to 750 mL with the remaining injection water, filter through a 0.22 μm PES filter membrane, and sterilize by moist heat at 121 °C for 15 min to obtain the gadobutrol injection.

[0070] Comparative Example 3

[0071] (1) Add 375 mL of fresh injection water to the preparation equipment, add 4500 μL of hydrochloric acid with a concentration of 1.0 mol / L, control the temperature at 40 - 50 °C, and mix evenly to obtain the first solution;

[0072] (2) Add 910 mg of trometamol to the first solution, control the temperature at 40 - 50 °C, and mix evenly to obtain the second solution;

[0073] (3) Add 402 mg of cobutamol calcium sodium to the second solution, control the temperature at 40 - 50 °C, and mix evenly to obtain the third solution;

[0074] (4) Add 490 g of gadobutrol monohydrate to the third solution, control the temperature at 40 - 50 °C, and mix evenly to obtain the mixed solution; make up the volume of the above mixed solution to 750 mL with the remaining injection water, filter through a 0.22 μm PES filter membrane, and sterilize by moist heat at 121 °C for 15 min to obtain the gadobutrol injection.

[0075] The gadobutrol injections prepared in Examples 1 - 3 were tested, and the test results are shown in Table 1 below.

[0076] Table 1 Test Results of Gadobutrol Injections in Examples 1 - 3

[0077]

[0078] Note: The heavy metal ion content in Table 1 is the content of the remaining heavy metal ions except free gadolinium ions, which are other metal ions brought in by production components and raw materials during the production process.

[0079] Impurity A in Table 1 is Impurity ZK00158723: Di - TOBO (4,10 - bis(2,3 - dihydroxy - 1 - hydroxymethylpropyl) - 1,4,7,10 - tetraazacyclododecane - 1,7 - diacetic acid); Impurity B in Table 1 is butrol; Impurity C in Table 1 is Impurity ZK00132534: Gd - D03A (complex of 1,4,7,10 - tetraazacyclododecane - 1,4,7 - triacetic acid and gadolinium).

[0080] As can be seen from Table 1, the content of free gadolinium ions in the gadobutrol injection prepared by the present invention is 0.00008 - 0.00012 mg / mL, and the content of free gadolinium ions is relatively low; the content of heavy metal ions is 15 - 19 ppm, the content of impurity B is 0.01 - 0.04%, and neither impurity A nor impurity C is detected, indicating that the quality of the prepared gadobutrol injection is qualified.

[0081] The stability tests were carried out on the gadobutrol injections prepared in Examples 1 - 3. Specifically, they were placed at 60 °C for 10 days (without additional control of other conditions), and the samples on the 10th day were taken for testing. The results are shown in Table 2.

[0082] Table 2 Results of stability tests of gadobutrol injection under high temperature conditions

[0083]

[0084] As can be seen from Table 2, for the gadobutrol injection prepared by the present invention under high temperature conditions, after 10 days of the test, there is no significant difference in the pH value and the content of free gadolinium ions, indicating good stability.

[0085] The stability tests were carried out on the gadobutrol injections prepared in Examples 1 - 3. Specifically, they were placed under strong light for 10 days (without additional control of other conditions), and the strong light conditions were: the illuminance was 4500 lx ± 500 lx, the total illuminance of the light source was not less than 1.2×10 6 lux·hr, and the energy of the near-ultraviolet lamp was not less than 200 W·hr / m 2 ; the samples on the 10th day were taken for testing. The results are shown in Table 3.

[0086] Table 3 Results of stability tests of gadobutrol injection under strong light conditions

[0087]

[0088]

[0089] As can be seen from Table 3, for the gadobutrol injection prepared by the preparation method of the present invention under strong light conditions, after 10 days of the test, there is no significant difference in the pH value and the content of free gadolinium, indicating good stability.

[0090] The gadobutrol injections prepared in Comparative Examples 1 - 3 were tested, and the test results are shown in Table 4 below.

[0091] Table 4 Test results of gadobutrol injections in Comparative Examples 1 - 3

[0092]

[0093] Comparing Example 3 with Comparative Example 1, it can be seen that Comparative Example 1 used a relatively high mixing temperature of 70 - 80°C. The content of free gadolinium ions in the prepared gadobutrol injection was 0.003 mg / mL, and the content of impurity B was 0.12%. The contents of both free gadolinium ions and impurity B were relatively high. The mixing temperature adopted in the present invention is 30 - 40°C, which is beneficial to reducing the contents of free gadolinium ions and impurities in the gadobutrol injection.

[0094] Comparing Example 3 with Comparative Example 2, it can be seen that Comparative Example 2 used hydrochloric acid to adjust the pH value finally. The content of free gadolinium ions in the prepared gadobutrol injection was 0.00022 mg / mL, and the content of free gadolinium ions was relatively high. The pH adjustment sequence of the present invention is different from that of Comparative Example 2. The pH regulator is first mixed evenly with part of the water, avoiding local over-acidity caused by the final adjustment, which may lead to the situation of gadolinium dissociation. From the above test results, it can be seen that adopting the preparation method of adjusting the pH value first can greatly reduce the content of free gadolinium ions in the gadobutrol injection.

[0095] Comparing Example 2 with Comparative Example 3, it can be seen that Comparative Example 3 used cobutamol calcium sodium as a metal ion complexing agent. The content of free gadolinium ions in the prepared gadobutrol injection was 0.0036 mg / mL, and the content of free gadolinium ions was relatively high. In Example 2 of the present invention, cobutamol calcium was used as a metal ion complexing agent, and the content of free gadolinium ions in the prepared gadobutrol injection was significantly reduced. From the above test results, it can be seen that using cobutamol calcium as a metal ion complexing agent can greatly reduce the content of free gadolinium ions in the gadobutrol injection.

[0096] Although the above embodiments have described the present invention in detail, they are only a part of the embodiments of the present invention, rather than all embodiments. People can also obtain other embodiments without creative efforts based on these embodiments, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A preparation method of gadobutrol injection, comprising the following steps: (1) Mix a pH regulator with a part of water to obtain a first solution; the pH regulator is hydrochloric acid, and the concentration of the pH regulator is 1.0 mol / L; (2) Mix trometamol with the first solution to obtain a second solution; mix cobutamol calcium with the second solution to obtain a third solution; Mix gadobutrol with the third solution and the remaining water to obtain gadobutrol injection; The mixing temperature in steps (1) to (2) is ≤ 50 °C; Based on the volume of gadobutrol injection as the unit volume, the concentration of gadobutrol is 0.59 - 0.66 g / mL, the concentration of cobutamol calcium is 0.46 - 0.52 mg / mL, the concentration of trometamol is 1.15 - 1.28 mg / mL, and the volume fraction of the pH regulator is 0.6%.

2. The preparation method according to claim 1, characterized in that, the mixing temperature in steps (1) to (2) is independently 20 - 50 °C.

3. The preparation method according to claim 1, characterized in that, the dosage ratio of the part of water to the remaining water is 2 - 3:3 - 2.

4. The preparation method according to claim 1, characterized in that, after mixing in step (2), it further includes filtering and sterilization in sequence.

5. The preparation method according to claim 4, characterized in that, the sterilization is moist heat sterilization; the sterilization temperature is 121 °C, and the sterilization time is 15 min.

6. The gadobutrol injection prepared by the preparation method according to any one of claims 1 - 5, and the content of free gadolinium ions in the gadobutrol injection < 0.0002 mg / mL.

7. The gadobutrol injection according to claim 6, characterized in that, the content of heavy metal ions other than free gadolinium ions in the gadobutrol injection ≤ 19 ppm.

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