A kind of gadoterate meglumine injection and preparation method thereof

Abstract

The present invention provides a gadoteric acid meglumine injection and a preparation method thereof, relating to the technical field of contrast agents. The present invention involves a first mixing of DOTA with a first portion of water to obtain a first solution; a second mixing of a second portion of water and a cosolvent with the first solution; and a pH adjuster to adjust the pH of the system to obtain a second solution; the pH adjuster comprises meglumine and an organic weak acid, the organic weak acid being at least one of citric acid, tartaric acid, and lactic acid; and a third mixing of the second solution, gadoteric acid meglumine, and the remaining water to obtain gadoteric acid meglumine injection; the gadoteric acid meglumine is injection-grade gadoteric acid meglumine. The method provided by the present invention is used to prepare gadoteric acid meglumine injection, which does not exhibit gadolinium ion leakage at low DOTA concentrations and has a low impurity content.

Description

Technical Field

[0001] The present invention relates to the technical field of contrast agents, and in particular to a gadoterate dimeglumine injection and a preparation method thereof. Background Art

[0002] Magnetic resonance imaging (MRI) typically uses protons, which are highly abundant in tissues. 1 H is its signal source. After applying radiofrequency energy, it generates magnetic resonance signals that are processed and imaged. It has the advantages of multi-parameter imaging, no ionizing radiation, and no traumatic damage, making it an ideal clinical examination method. In MRI, T1 relaxation (longitudinal relaxation) and T2 relaxation (transverse relaxation) occur simultaneously. The time of the two relaxations will affect the intensity of the nuclear magnetic resonance signal. The main component of gadoteric acid meglumine injection is gadoteric acid meglumine, which is a complex of lanthanide metals. Gadolinic acid has paramagnetism, which can shorten the time of T1 relaxation and T2 relaxation, and increase the image intensity of nuclear magnetic resonance. Gadolinic acid will not pass through the intact blood-brain barrier and will not increase the nuclear magnetic resonance signal of the normal brain and normal blood-brain barrier. However, gadoteric acid can pass through abnormal blood-brain barriers or abnormal blood vessels, enhance the nuclear magnetic resonance signal of diseased tissues, and improve the MRI contrast between lesions and normal tissues. Therefore, gadoteric acid meglumine injection is usually used as a contrast agent for nuclear magnetic resonance examinations.

[0003] Gadolinium is a heavy metal element of the lanthanide series, and free gadolinium ions are toxic to human tissues. The relevant agencies of the China Food and Drug Administration, the U.S. Food and Drug Administration (FDA), and the European Medicines Agency (EMA) have issued warnings that gadolinium-containing contrast agents will increase the risk of nephrogenic systemic fibrosis (NSF) in patients with impaired drug clearance, and its pathology may be associated with a small number of free gadolinium ions (i.e., gadolinium ions that are not complexed in the body). Gadoteric acid dimeglumine injection is a macrocyclic chelated nonspecific gadolinium-containing contrast agent, which contains an excess of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetracarboxylic acid (DOTA, a macrocyclic ligand) to chelate free gadolinium ions to prevent the risk of poisoning caused by gadolinium ion leakage. If the amount of DOTA added is insufficient, other metal ions such as Ca in the system may be present during use. 2+ 、Zn 2+ The free DOTA itself is also toxic, with an LD50 of 0.18 mmol / kg, and a large amount of free DOTA can react with Ca in the blood. 2+The combination of DOTA and gadolinium oxide can cause a decrease in blood calcium, leading to hypocalcemia. Therefore, excessive DOTA intake is also detrimental to human health. Furthermore, existing technologies typically use gadolinium oxide as a starting material (e.g., patents CN101977633B and CN110114093A). However, injectable-grade gadolinium oxide APIs are currently unavailable, and non-injectable-grade gadolinium oxide raw materials contain a high level of impurities, resulting in a high impurity content in the product. Summary of the Invention

[0004] The object of the present invention is to provide a gadoteric acid meglumine injection and a preparation method thereof. When the gadoteric acid meglumine injection is prepared by the method provided by the present invention, there will be no gadolinium ion leakage problem at low DOTA concentrations, and the impurity content is low.

[0005] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0006] The present invention provides a method for preparing gadoterate dimeglumine injection, comprising the following steps:

[0007] The DOTA is first mixed with the first portion of water to obtain a first solution; wherein the amount of DOTA in the gadoterate meglumine injection is 0.001 to 0.25 g / 1000 mL;

[0008] performing a second mixing of the second portion of water and the cosolvent with the first solution, and adjusting the pH value of the system with a pH adjuster to obtain a second solution; the pH adjuster comprises meglumine and an organic weak acid, and the organic weak acid is at least one of citric acid, tartaric acid, and lactic acid;

[0009] The second solution, gadoterate meglumine and the remaining water are mixed for a third time to obtain gadoterate meglumine injection; the gadoterate meglumine is injection-grade gadoterate meglumine.

[0010] Preferably, the concentration of DOTA in the first solution is 5-10 wt %.

[0011] Preferably, the amount of the cosolvent in the gadoterate dimeglumine injection is 5 to 10 g / 1000 mL.

[0012] Preferably, the second portion of water is filled with nitrogen before use to control the dissolved oxygen concentration to be ≤4 ppm.

[0013] Preferably, the second portion of water accounts for 55-65% of the total amount of water in the gadoterate dimeglumine injection.

[0014] Preferably, the pH value of the second solution is 7.5-8.0.

[0015] Preferably, the mass ratio of meglumine to organic weak acid is (1-4):1.

[0016] Preferably, the third mixing further includes filtering, filling, filling the headspace with nitrogen and sterilizing in sequence.

[0017] The present invention provides a gadoterate meglumine injection prepared by the preparation method described in the above technical solution, wherein the content of free DOTA in the gadoterate meglumine injection is ≤0.025wt%, and the impurity content is ≤0.1wt%.

[0018] Preferably, the pH value of the gadoterate dimeglumine injection is 7.5-8.0.

[0019] The present invention provides a preparation method of gadoteric acid meglumine injection, comprising the following steps: first mixing DOTA with a first portion of water to obtain a first solution; wherein the amount of DOTA in the gadoteric acid meglumine injection is 0.001-0.25 g / 1000 mL; second mixing of a second portion of water and a cosolvent with the first solution, and adjusting the pH value of the system with a pH regulator to obtain a second solution; wherein the pH regulator comprises meglumine and an organic weak acid, wherein the organic weak acid is at least one of citric acid, tartaric acid, and lactic acid; and third mixing of the second solution, gadoteric acid meglumine, and remaining water to obtain gadoteric acid meglumine injection; wherein the gadoteric acid meglumine is injection-grade gadoteric acid meglumine. The present invention adopts an organic weak acid and meglumine to form a pH buffer system, and gadoteric acid meglumine is added last, thereby ensuring that the prepared gadoteric acid meglumine injection does not have the problem of gadolinium ion leakage at a low DOTA concentration and has a low impurity content; at the same time, the cosolvent used in the present invention can play a solubilizing role, ensure that the system has good stability, and ensure that the clarity of the gadoteric acid meglumine injection meets the requirements. DETAILED DESCRIPTION

[0020] The present invention provides a method for preparing gadoterate dimeglumine injection, comprising the following steps:

[0021] The DOTA is first mixed with the first portion of water to obtain a first solution; wherein the amount of DOTA in the gadoterate meglumine injection is 0.001 to 0.25 g / 1000 mL;

[0022] performing a second mixing of the second portion of water and the cosolvent with the first solution, and adjusting the pH value of the system with a pH adjuster to obtain a second solution; the pH adjuster comprises meglumine and an organic weak acid, and the organic weak acid is at least one of citric acid, tartaric acid, and lactic acid;

[0023] The second solution, gadoterate meglumine and the remaining water are mixed for a third time to obtain gadoterate meglumine injection; the gadoterate meglumine is injection-grade gadoterate meglumine.

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

[0025] First, the raw materials for preparing the gadoteric acid meglumine injection of the present invention are described. The raw materials for preparing the gadoteric acid meglumine injection of the present invention include gadoteric acid meglumine, DOTA, a cosolvent, a pH regulator, and water.

[0026] The raw materials for preparing the gadoterate meglumine injection of the present invention include gadoterate meglumine, and the gadoterate meglumine is injection-grade gadoterate meglumine; the amount of gadoterate meglumine in the gadoterate meglumine injection is preferably 376.9 g / 1000 mL. The present invention uses injection-grade gadoteric acid meglumine to prepare gadoteric acid meglumine injection, controls the impurities and bacterial endotoxin levels of the raw materials, and avoids the risk of free gadolinium ion contamination caused by the replacement of gadolinium ions by other metal elements in gadolinium oxide compared to the prior art. At the same time, the preparation of gadoteric acid meglumine injection has fewer process steps and does not require complicated multiple flushing and ultrafiltration operations, thereby reducing the risk of introduction of impurities and bacterial contamination, and there is no problem of ultrafiltration module components migrating into the contaminated liquid. The operation is simple, which is conducive to cost saving, and avoids the problems of complicated processes, long cycles, and many by-products in the prior art of preparing gadoteric acid meglumine injection through multiple chemical reactions of gadolinium oxide. At the same time, the product quality of gadoteric acid meglumine injection is improved, and the safety of clinical medication for patients is guaranteed.

[0027] The raw materials for preparing the gadoteric acid meglumine injection of the present invention include DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetracarboxylic acid). The amount of DOTA used in the gadoteric acid meglumine injection is 0.001 to 0.25 g / 1000 mL, preferably 0.01 to 0.2 g / 1000 mL, and more preferably 0.015 to 0.1 g / 1000 mL. The low amount of DOTA used in the present invention can avoid the toxic side effects caused by excessive use of DOTA.

[0028] The raw materials for preparing the gadoteric acid meglumine injection of the present invention include a cosolvent, preferably propylene glycol or polyethylene glycol. The amount of the cosolvent in the gadoteric acid meglumine injection is preferably 5 to 10 g / 1000 mL, more preferably 6 to 8 g / 1000 mL. In the present invention, the addition of the cosolvent, preferably controlling its amount within the above range, facilitates achieving the required clarity of the gadoteric acid meglumine injection.

[0029] The raw materials for preparing the gadoteric acid meglumine injection of the present invention include a pH regulator, which includes meglumine and an organic weak acid. The organic weak acid is at least one of citric acid, tartaric acid and lactic acid, specifically citric acid, tartaric acid or lactic acid, or citric acid and tartaric acid are used together; when the organic weak acid is citric acid and tartaric acid, the mass ratio of citric acid to tartaric acid is preferably (1-3):1, more preferably (1-2):1. In the present invention, the mass ratio of meglumine to the organic weak acid is preferably (1-4):1, more preferably (1.25-3):1. In the present invention, the pH regulator is actually a pH buffer system composed of an organic weak base (meglumine) and an organic weak acid, wherein the organic weak acid has a certain ability to complex metal ions, thereby avoiding the release of gadolinium ions caused by replacement of other metal ions, so that gadolinium ion leakage does not occur at low DOTA concentrations, thereby reducing the risk of NFS in patients.

[0030] The raw materials for preparing the gadoteric acid dimeglumine injection of the present invention include water, and the water is preferably water for injection. The present invention divides the water into three parts, namely a first part of water, a second part of water, and the remaining water. In the present invention, the first part of water is used to dissolve DOTA, that is, it is used in the form of a DOTA aqueous solution, which expands the sample weighing amount and avoids the problem of inaccurate feeding caused by moisture absorption and the small sample weighing amount in the prior art. In the present invention, the second part of water is used to dissolve the other raw materials for preparation, and finally the remaining water is used to make up to the required volume; the amount of each part of water will be described in detail later.

[0031] The preparation method of the gadoterate meglumine injection of the present invention is described below.

[0032] In the present invention, DOTA is first mixed with a first portion of water to obtain a first solution. In the present invention, the concentration of DOTA in the first solution is preferably 5 to 10 wt%, more preferably 6 to 8 wt%. The amount of the first portion of water used is sufficient to ensure that the DOTA concentration in the first solution meets the above requirements.

[0033] After obtaining the first solution, the present invention performs a second mixing of the first solution with a second portion of water and a cosolvent, and adjusts the pH of the system using a pH adjuster to obtain a second solution. In the present invention, the second portion of water is preferably nitrogen-filled before use, preferably controlling the dissolved oxygen concentration to ≤4 ppm. The second portion of water preferably accounts for 55-65%, more preferably 60%, of the total water content in the gadoteric acid dimeglumine injection. In the present invention, the temperature of the second mixing is preferably 20-60°C, more preferably 50-60°C; the second mixing is preferably performed under stirring conditions. The present invention does not specifically limit the stirring rate, as long as the components are thoroughly mixed. In the present invention, the amount of the pH adjuster is sufficient to ensure that the second solution meets the required pH requirements. The pH of the second solution is preferably 7.5-8.0, more preferably 7.7-7.8. The present invention preferably controls the pH of the second solution within the above range to prevent DOTA from being in an overly acidic environment, which could lead to the liberation of gadolinium ions and the degradation of the main drug to produce impurities, thereby improving product quality and ensuring patient safety.

[0034] After obtaining the second solution, the present invention performs a third mixing of the second solution, gadoteric acid meglumine and the remaining water to obtain gadoteric acid meglumine injection. In the present invention, the temperature of the third mixing is preferably 20 to 60°C, more preferably 50 to 60°C; the third mixing is preferably carried out under stirring conditions, and the present invention has no special restrictions on the stirring rate, as long as the components are fully mixed. When preparing the gadoteric acid meglumine injection according to the present invention, DOTA, a cosolvent and a pH regulator are first added so that the pH value of the solution is relatively stable at this time, forming a stable solution system, and finally gadoteric acid meglumine is added, which is beneficial to avoid the appearance of free gadolinium ions in the final gadoteric acid meglumine injection and reduce impurities produced by degradation of the main drug, thereby improving the quality of the product and ensuring the safety of the patient's medication.

[0035] In the present invention, after the third mixing, it is preferred that filtration, filling, headspace nitrogen filling and sterilization are carried out in sequence. In the present invention, the filter membrane used for the 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 filling, and methods well known to those skilled in the art can be used; the specification of the gadoteric acid dimeglumine injection in the present invention is preferably 15 mL / bottle. In the present invention, the headspace nitrogen filling is preferably based on controlling the residual oxygen ≤ 9%. In the present invention, the sterilization is preferably moist heat sterilization; the sterilization temperature is preferably 121°C, and the time is preferably 15 min; the sterilization out-of-box temperature is preferably ≤ 60°C.

[0036] The present invention provides a gadoteric acid meglumine injection prepared by the preparation method of the above technical solution, wherein the content of free DOTA in the gadoteric acid meglumine injection is ≤0.025wt%, specifically 0.001-0.025wt%; the impurity content (specifically the total impurity content) is ≤0.1wt%, specifically 0.09-0.10wt%, wherein the maximum single impurity content is ≤0.012wt%, specifically 0.010-0.012wt%. In the present invention, the pH value of the gadoteric acid meglumine injection is preferably 7.5-8.0, specifically 7.6-7.9, and further 7.7-7.8. In the present invention, the gadoteric acid meglumine injection is a colorless, clear liquid, clear, and no free gadolinium ions are detected.

[0037] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions of the present invention. Obviously, the embodiments described are only some of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0038] Example 1

[0039] Mixing 0.01 g of DOTA with a first portion of water for injection to obtain a first solution, wherein the DOTA concentration in the first solution is 10 wt %;

[0040] The second portion of water for injection was filled with nitrogen to control the dissolved oxygen to ≤4 ppm, and the preparation temperature was controlled at 50-60°C. 10 g of propylene glycol and the first solution were then added and stirred to mix evenly. Lactic acid and meglumine (lactic acid to meglumine mass ratio of 1:1) were then added in sequence to adjust the pH value of the system to 7.5 to obtain a second solution; wherein the second portion of water for injection accounted for 60% of the total amount of water for injection;

[0041] The second solution was mixed with 376.9 g of gadoterate dimeglumine and stirred to dissolve to obtain a third solution;

[0042] The third solution was diluted to 1000 mL using the third portion of water for injection (i.e., the remaining water), finely filtered through a 0.22 μm PES filter membrane, and then bottled in 15 mL / bottles. The headspace was filled with nitrogen to control the residual oxygen to ≤ 9%. Finally, the solution was sterilized by moist heat at 121° C. for 15 min with an outlet temperature of ≤ 60° C. to obtain gadoterate dimeglumine injection.

[0043] Example 2

[0044] Mixing 0.25 g of DOTA with a first portion of water for injection to obtain a first solution, wherein the DOTA concentration in the first solution is 5 wt %;

[0045] The second portion of water for injection was filled with nitrogen to control the dissolved oxygen to ≤4 ppm, and the preparation temperature was controlled at 50-60°C. 10 g of propylene glycol and the first solution were then added and stirred to mix evenly. Tartaric acid and meglumine (the mass ratio of tartaric acid to meglumine was 1:4) were then added in sequence to adjust the pH value of the system to 8.0 to obtain a second solution; wherein the second portion of water for injection accounted for 60% of the total amount of water for injection;

[0046] The second solution was mixed with 376.9 g of gadoterate dimeglumine and stirred to dissolve to obtain a third solution;

[0047] The third solution was diluted to 1000 mL with the third portion of water for injection (i.e., the remaining water), filtered through a 0.22 μm PES filter membrane, and then bottled in 15 mL / bottles. The headspace was filled with nitrogen to control the residual oxygen to ≤ 9%; finally, the solution was sterilized by moist heat at 121° C. for 15 min with an outlet temperature of ≤ 60° C. to obtain gadoterate meglumine injection.

[0048] Example 3

[0049] Mixing 0.1 g of DOTA with a first portion of water for injection to obtain a first solution, wherein the DOTA concentration in the first solution is 10 wt %;

[0050] The second portion of water for injection was filled with nitrogen to control the dissolved oxygen to ≤4 ppm, and the preparation temperature was controlled at 50-60°C. Then, 8 g of propylene glycol and the first solution were added and stirred to mix evenly. Then, citric acid, tartaric acid, and meglumine (the mass ratio of citric acid, tartaric acid, and meglumine was 1:1:2.5) were added in sequence to adjust the pH value of the system to 7.7 to obtain a second solution; wherein, the second portion of water for injection accounted for 60% of the total amount of water for injection;

[0051] The second solution was mixed with 376.9 g of gadoterate dimeglumine and stirred to dissolve to obtain a third solution;

[0052] The third solution was diluted to 1000 mL using the third portion of water for injection (i.e., the remaining water), finely filtered through a 0.22 μm PES filter membrane, and then bottled in 15 mL / bottles. The headspace was filled with nitrogen to control the residual oxygen to ≤ 9%; finally, the solution was sterilized by moist heat at 121° C. for 15 min with an outlet temperature of ≤ 60° C. to obtain gadoterate meglumine injection.

[0053] Example 4

[0054] Mixing 0.015 g of DOTA with a first portion of water for injection to obtain a first solution, wherein the DOTA concentration in the first solution is 8 wt %;

[0055] The second portion of water for injection was filled with nitrogen to control the dissolved oxygen to ≤4 ppm, and the preparation temperature was controlled at 50-60°C. Then, 8 g of propylene glycol and the first solution were added and stirred to mix evenly. Then, citric acid and meglumine (the mass ratio of citric acid to meglumine was 1:3) were added in sequence to adjust the pH value of the system to 7.7 to obtain a second solution; wherein the second portion of water for injection accounted for 60% of the total amount of water for injection;

[0056] The second solution was mixed with 376.9 g of gadoterate dimeglumine and stirred to dissolve to obtain a third solution;

[0057] The second solution was diluted to 1000 mL using the third portion of water for injection (i.e., the remaining water), finely filtered through a 0.22 μm PES filter membrane, and then bottled in 15 mL / bottles. The headspace was filled with nitrogen to control the residual oxygen to ≤ 9%. Finally, the solution was sterilized by moist heat at 121° C. for 15 min with an outlet temperature of ≤ 60° C. to obtain gadoterate meglumine injection.

[0058] Comparative Example 1

[0059] Mixing 0.015 g of DOTA with a first portion of water for injection to obtain a first solution, wherein the DOTA concentration in the first solution is 8 wt %;

[0060] The second portion of water for injection was filled with nitrogen to control the dissolved oxygen to ≤4 ppm, and the preparation temperature was controlled at 50-60°C. Then, 10 g of propylene glycol and the first solution were added and stirred to mix evenly. Then, meglumine was added to adjust the pH value of the system to 7.5 to obtain a second solution; wherein the second portion of water for injection accounted for 60% of the total amount of water for injection;

[0061] The second solution was mixed with 376.9 g of gadoterate dimeglumine and stirred to dissolve to obtain a third solution;

[0062] The third solution was diluted to 1000 mL using the third portion of water for injection (i.e., the remaining water for injection), finely filtered through a 0.22 μm PES filter membrane, and then bottled in a size of 15 mL / bottle. The headspace was filled with nitrogen to control the residual oxygen to ≤ 9%; finally, the solution was sterilized by moist heat at 121° C. for 15 min with an outlet temperature of ≤ 60° C. to obtain gadoterate meglumine injection.

[0063] Comparative Example 2

[0064] Mixing 0.015 g of DOTA with a first portion of water for injection to obtain a first solution, wherein the DOTA concentration in the first solution is 8 wt %;

[0065] The second portion of water for injection is filled with nitrogen to control the dissolved oxygen to ≤4 ppm, and the preparation temperature is controlled at 50-60°C. The first solution is then added and stirred to mix evenly. Citric acid and meglumine (the mass ratio of citric acid to meglumine is 1:3) are then added in sequence to adjust the pH value of the system to 7.7 to obtain a second solution; wherein the second portion of water for injection accounts for 60% of the total amount of water for injection;

[0066] The second solution was mixed with 376.9 g of gadoterate dimeglumine and stirred to dissolve to obtain a third solution;

[0067] The third solution was diluted to 1000 mL using the third portion of water for injection (i.e., the remaining water for injection), finely filtered through a 0.22 μm PES filter membrane, and then bottled in a size of 15 mL / bottle. The headspace was filled with nitrogen to control the residual oxygen to ≤ 9%; finally, the solution was sterilized by moist heat at 121° C. for 15 min with an outlet temperature of ≤ 60° C. to obtain gadoterate meglumine injection.

[0068] Comparative Example 3

[0069] Mixing 0.015 g of DOTA with a first portion of water for injection to obtain a first solution, wherein the DOTA concentration in the first solution is 8 wt %;

[0070] The second portion of water for injection was filled with nitrogen to control the dissolved oxygen to ≤4 ppm, and the solution temperature was controlled at 50-60°C. Then, 376.9 g of gadoteric acid meglumine was added and stirred to dissolve to obtain a second solution; wherein the second portion of water for injection accounted for 60% of the total amount of water for injection;

[0071] The second solution was mixed with 8 g of propylene glycol and the first solution, and then citric acid and meglumine (the mass ratio of citric acid to meglumine was 1:3) were added to adjust the pH value of the system to 7.7 to obtain a third solution;

[0072] The third solution was diluted to 1000 mL using the third portion of water for injection, finely filtered through a 0.22 μm PES filter membrane, and then bottled in 15 mL / bottles. The headspace was filled with nitrogen to control the residual oxygen to ≤ 9%. Finally, the solution was sterilized by moist heat at 121° C. for 15 min with an outlet temperature of ≤ 60° C. to obtain gadoterate meglumine injection.

[0073] The gadoteric acid meglumine injections prepared in Examples 1 to 4 and Comparative Examples 1 to 3 were subjected to performance tests. The fresh gadoteric acid meglumine injection (0 day) obtained after preparation was tested, and the results are shown in Table 1. The gadoteric acid meglumine injection obtained after preparation was stored at 40° C. for 3 months, and the results are shown in Table 2.

[0074] Table 1 Test results of fresh gadoteric acid meglumine injection (0 day) prepared in Examples and Comparative Examples

[0075]

[0076] Table 2 Test results of gadoteric acid meglumine injection prepared in Examples and Comparative Examples stored at 40°C for 3 months

[0077]

[0078] As can be seen from Tables 1 and 2, in Comparative Example 1, only meglumine was used as a pH regulator. The gadoterate meglumine injection prepared therefrom had a high free gadolinium ion content and impurity content when stored at 40°C for 3 months at 0 days. However, citric acid, tartaric acid, and lactic acid all have metal ion complexing effects, which can complex metal ions such as iron and zinc to prevent metal ions from replacing gadolinium and causing gadolinium ion release, while ensuring that gadolinium ions will not be free at low DOTA concentrations.

[0079] Propylene glycol was not used in Comparative Example 2. When the prepared gadoteric acid meglumine injection was stored at 0 day and 40°C for 3 months, the clarity decreased and the turbidity was deeper than that of standard solution No. 1 (specifically recorded in General Chapter 0902 of the 2020 edition of the Chinese Pharmacopoeia); a small amount of gadoteric acid will be free in the gadoteric acid meglumine injection during the storage process, and the solubility of gadoteric acid is poor, which will cause the clarity of the gadoteric acid meglumine injection to decrease. Propylene glycol is a cosolvent and can play a solubilizing role, so that the clarity of the gadoteric acid meglumine injection meets the requirements.

[0080] In Comparative Example 3, gadoteric acid meglumine is added first, and then DOTA and the pH regulator are added. The gadoteric acid meglumine injection prepared therefrom has a high impurity content when stored for 3 months at 0 days and 40°C. DOTA can act as a stabilizer. By first adding DOTA and adjusting the pH value of the system, a stable solution system can be provided before the addition of gadoteric acid meglumine. At this time, the addition of the raw material can make the solution system more stable.

[0081] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A method for preparing gadoteric acid meglumine injection, comprising the following steps: The DOTA is first mixed with the first portion of water to obtain a first solution; wherein the amount of DOTA in the gadoterate meglumine injection is 0.001 to 0.25 g / L; performing a second mixing of the second portion of water and the cosolvent with the first solution, and adjusting the pH value of the system with a pH adjuster to obtain a second solution; the cosolvent is propylene glycol; the pH adjuster comprises meglumine and an organic weak acid, and the organic weak acid is at least one of citric acid, tartaric acid, and lactic acid; The second solution, gadoterate meglumine and the remaining water are mixed for a third time to obtain gadoterate meglumine injection; the gadoterate meglumine is injection-grade gadoterate meglumine.

2. The preparation method according to claim 1, characterized in that The concentration of DOTA in the first solution is 5-10 wt %.

3. The preparation method according to claim 1, characterized in that The dosage of the cosolvent in the gadoterate meglumine injection is 5 to 10 g / L.

4. The preparation method according to claim 1, characterized in that The second portion of water is filled with nitrogen before use to control the dissolved oxygen concentration to be ≤4 ppm.

5. The preparation method according to claim 1, 3 or 4, characterized in that: The second portion of water accounts for 55-65% of the total amount of water in the gadoterate dimeglumine injection.

6. The preparation method according to claim 5, characterized in that The pH value of the second solution is 7.5-8.

0.

7. The preparation method according to claim 6, characterized in that The mass ratio of the meglumine to the organic weak acid is (1-4):

1.

8. The preparation method according to claim 1, characterized in that After the third mixing, the process also includes filtering, filling, filling the headspace with nitrogen and sterilizing.

9. The gadoterate meglumine injection prepared by the preparation method according to any one of claims 1 to 8, wherein the content of free DOTA in the gadoterate meglumine injection is ≤0.025 wt%, and the impurity content is ≤0.1 wt%.

10. The gadoteric acid dimeglumine injection according to claim 9, characterized in that: The pH value of the gadoterate dimeglumine injection is 7.5-8.0.

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