Gadobutrol injection and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a gadobutrol injection and a preparation method thereof. The gadobutrol injection comprises gadobutrol, sodium calcobutrol, arginine, a pH regulator and water for injection, the pH regulator is selected from one or more of citric acid, phosphoric acid, hydrochloric acid, acetic acid and tartaric acid, and the pH value of the injection is regulated to be about 6.6-8.0. The gadobutrol injection disclosed by the invention is good in stability, free gadolinium content meets requirements, tromethamine is prevented from being used, and liquid medicine is good in safety.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a gadobutrol injection and a preparation method thereof. Background Art

[0002] Gadobutrol injection is a diagnostic drug developed and manufactured by Bayer Schering Pharma. It was approved by the FDA on March 14, 2011, becoming the sixth gadolinium-based contrast agent (GB-CA) approved by the FDA for central nervous system magnetic resonance imaging (CNS) imaging. Its trade name is Gasovist, and its chemical name is 10-(2,3-dihydroxy-1-hydroxymethylpropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid gadolinium complex. As a second-generation gadolinium contrast agent, gadobutrol is an extracellularly distributed, non-tissue-specific, non-ionic, macrocyclic paramagnetic gadolinium chelator. Its high concentration and high relaxivity offer unique advantages in CNS contrast-enhanced magnetic resonance imaging (CE-MRI) (including brain and spine imaging) and contrast-enhanced magnetic resonance angiography (CE-MRA).

[0003] The publicly available Gasovist instructions reveal that the excipients for gadobutrol injection include tromethamine, sodium calcobutrol, hydrochloric acid, and water for injection. From a clinical perspective, this type of injection presents the following issues: Tromethamine, an excipient, acts as a pH buffer, and its side effects are significant. It can cause hypoglycemia, hypotension, nausea, vomiting, and, in severe cases, respiratory depression. If it leaks outside blood vessels, it can cause tissue necrosis and thrombophlebitis. To address the side effects of tromethamine, patent CN106620726A optimized the pH buffer, replacing tromethamine with disodium hydrogen phosphate to achieve a more stable gadobutrol injection. However, the introduction of 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).

[0004] Therefore, there is still a need to develop a gadobutrol injection with good stability and high safety and a preparation method thereof. Summary of the Invention

[0005] To solve the above technical problems, the present invention provides a gadobutrol injection and a preparation method thereof. The gadobutrol injection of the present invention uses a specific pH buffer and a pH adjuster to adjust the pH value of the injection, maintain its stability during the sterilization process, and effectively control the content of free gadolinium.

[0006] The technical solution adopted in the present invention is as follows:

[0007] A gadobutrol injection comprises the following components: gadobutrol, colbutrol calcium sodium, arginine, a pH regulator and water for injection; the pH regulator adjusts the pH value of the injection to about 6.6-about 8.0.

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

[0009] Further preferably, the pH adjuster is selected from citric acid, and the pH value of the injection solution is adjusted to about 7.0-about 7.5.

[0010] Preferably, the injection comprises 600-610 g of gadobutrol, 510-515 mg of calcobutrol sodium, 2.0-2.8 g of arginine, an appropriate amount of citric acid, and water for injection per 1000 mL of injection; the amount of citric acid is such that the pH value of the injection is adjusted to about 7.0 to about 7.5.

[0011] Particularly preferably, the composition of the injection is as follows: per 1000 mL of injection, it contains 604.72 g of gadobutrol, 513 mg of sodium calcobutrol, 2.42 g of arginine, an appropriate amount of citric acid, and water for injection; the amount of citric acid is such that the pH value of the injection is adjusted to about 7.0 to about 7.5.

[0012] The present invention also provides a method for preparing the gadobutrol injection, which specifically comprises the following steps:

[0013] Step 1: Weigh 80-90% of the prescribed amount of water for injection, add the prescribed amount of colostrum calcium sodium and arginine, and stir to dissolve at room temperature to obtain solution 1;

[0014] Step 2: Heat Solution 1 to 40-50° C., add the prescribed amount of gadobutrol, and stir to dissolve completely. After the solution is cooled to room temperature, adjust the pH value of the solution to about 6.6-about 8.0 with a pH adjuster to obtain Solution 2;

[0015] Step 3: Add the remaining amount of water for injection to solution 2 to make up the volume, filter with a microporous membrane, and fill;

[0016] Step 4: Sterilization and packaging.

[0017] Preferably, the pH adjuster in step 2 is selected from one or more of citric acid, phosphoric acid, hydrochloric acid, acetic acid, and tartaric acid, more preferably citric acid.

[0018] Preferably, the pH is about 7.0 to about 7.5.

[0019] Preferably, the water used for the injection in step 1 is 90% of the prescribed amount.

[0020] Preferably, the sterilization in step 4 is carried out at 121° C. for 15 minutes.

[0021] Compared with the prior art, the technical solution of the present invention has the following beneficial technical effects: (1) the gadobutrol injection of the present invention has good stability, and the content of free gadolinium is controlled at a medically acceptable low level; (2) the use of tromethamine is avoided, thereby improving the safety of the drug solution. DETAILED DESCRIPTION

[0022] In order to better understand the technical solution of the present invention, the technical solution of the present invention is further described below in conjunction with specific embodiments. The embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0023] The term "about" refers to an acceptable error for a particular value as determined by one of ordinary skill in the art, such as an acceptable range of ±0.05 for pH.

[0024] Example 1

[0025] Prescription (based on 1000mL): Gadobutrol 604.72g, Calcobutrol sodium 513mg, arginine 2.42g, and appropriate amount of citric acid.

[0026] Preparation method: Add 90% of the total water volume of the prescription into the liquid dispensing equipment, add the prescribed amount of sodium arginine and calcium benzoate, and stir to dissolve at room temperature; heat the solution to 40-50°C, add the prescribed amount of gadobutrol, stir to dissolve completely and mix thoroughly; after the solution is cooled to room temperature, add citric acid to adjust the pH value of the solution to approximately 7.0, and add the remaining prescribed amount of water for injection to the volume; filter the liquid through a 0.22μm sterilizing grade filter cartridge and fill; finally, sterilize at 121°C for 15 minutes.

[0027] Example 2

[0028] Prescription (based on 1000mL): Gadobutrol 604.72g, Calcobutrol sodium 513mg, arginine 2.42g, and appropriate amount of citric acid.

[0029] Preparation method: Add 80% of the total water volume of the prescription into the liquid dispensing equipment, add the prescribed amount of sodium arginine and calcium benzoate, and stir to dissolve at room temperature; heat the solution to 40-50°C, add the prescribed amount of gadobutrol, stir to dissolve completely and mix thoroughly; after the solution is cooled to room temperature, add citric acid to adjust the pH value of the solution to approximately 7.5, and add the remaining prescribed amount of water for injection to the volume; filter the liquid through a 0.22μm sterilizing grade filter cartridge and fill; finally, sterilize at 121°C for 15 minutes.

[0030] Example 3

[0031] Prescription (based on 1000mL): Gadobutrol 604.72g, Calcobutrol sodium 513mg, arginine 2.42g, and appropriate amount of citric acid.

[0032] Preparation method: Add 80% of the total water volume of the prescription into the liquid dispensing equipment, add the prescribed amount of sodium arginine and calcium benzoate, and stir to dissolve at room temperature; heat the solution to 40-50°C, add the prescribed amount of gadobutrol, stir to dissolve completely and mix thoroughly; after the solution is cooled to room temperature, add citric acid to adjust the pH value of the solution to approximately 6.6, and add the remaining prescribed amount of water for injection to the volume; filter the liquid through a 0.22μm sterilizing grade filter cartridge and fill; finally, sterilize at 121°C for 15 minutes.

[0033] Example 4

[0034] Prescription (based on 1000mL): Gadobutrol 604.72g, Calcobutrol sodium 513mg, arginine 2.42g, and appropriate amount of citric acid.

[0035] Preparation method: Add 80% of the total water volume of the prescription into the liquid dispensing equipment, add the prescribed amount of sodium arginine and calcium benzoate, and stir to dissolve at room temperature; heat the solution to 40-50°C, add the prescribed amount of gadobutrol, stir to dissolve completely and mix thoroughly; after the solution is cooled to room temperature, add citric acid to adjust the pH value of the solution to approximately 8.0, and add the remaining prescribed amount of water for injection to the volume; filter the liquid through a 0.22μm sterilizing grade filter cartridge and fill; finally, sterilize at 121°C for 15 minutes.

[0036] Example 5

[0037] Prescription (based on 1000mL): Gadobutrol 604.72g, Calcobutrol sodium 513mg, arginine 2.0g, and appropriate amount of citric acid.

[0038] Preparation method: Add 90% of the total water volume of the prescription into the liquid dispensing equipment, add the prescribed amount of sodium arginine and calcium benzoate, and stir to dissolve at room temperature; heat the solution to 40-50°C, add the prescribed amount of gadobutrol, stir to dissolve completely and mix thoroughly; after the solution is cooled to room temperature, add citric acid to adjust the pH value of the solution to approximately 7.0, and add the remaining prescribed amount of water for injection to the volume; filter the liquid through a 0.22μm sterilizing grade filter cartridge and fill; finally, sterilize at 121°C for 15 minutes.

[0039] Example 6

[0040] Prescription (based on 1000mL): Gadobutrol 604.72g, Calcobutrol sodium 513mg, arginine 2.8g, and appropriate amount of citric acid.

[0041] Preparation method: Add 90% of the total water volume of the prescription into the liquid dispensing equipment, add the prescribed amount of sodium arginine and calcium benzoate, and stir to dissolve at room temperature; heat the solution to 40-50°C, add the prescribed amount of gadobutrol, stir to dissolve completely and mix thoroughly; after the solution is cooled to room temperature, add citric acid to adjust the pH value of the solution to approximately 7.0, and add the remaining prescribed amount of water for injection to the volume; filter the liquid through a 0.22μm sterilizing grade filter cartridge and fill; finally, sterilize at 121°C for 15 minutes.

[0042] Comparative Example 1

[0043] Prescription (based on 1000mL): Gadobutrol 604.72g, Calcobutrol sodium 513mg, Lysine 2.42g, and appropriate amount of citric acid.

[0044] Preparation method: Add 90% of the total water volume of the prescription into the liquid dispensing equipment, add the prescribed amount of sodium calcobutrol and lysine, and stir to dissolve at room temperature; heat the solution to 40-50°C, add the prescribed amount of gadobutrol, stir to dissolve completely and mix thoroughly; after the solution is cooled to room temperature, add citric acid to adjust the pH value of the solution to approximately 7.0, and add the remaining prescribed amount of water for injection to the volume; filter the liquid through a 0.22μm sterilizing grade filter cartridge and fill; finally, sterilize at 121°C for 15 minutes.

[0045] Comparative Example 2

[0046] Prescription (based on 1000mL): Gadobutrol 604.72g, Calcobutrol sodium 513mg, histidine 2.42g, and appropriate amount of citric acid.

[0047] Preparation method: Add 90% of the total water volume of the prescription into the liquid dispensing equipment, add the prescribed amount of sodium calcobutrol and histidine, and stir to dissolve at room temperature; heat the solution to 40-50°C, add the prescribed amount of gadobutrol, stir to dissolve completely and mix thoroughly; after the solution is cooled to room temperature, add citric acid to adjust the pH value of the solution to approximately 7.0, and add the remaining prescribed amount of water for injection to the volume; filter the liquid through a 0.22μm sterilizing grade filter cartridge and fill; finally, sterilize at 121°C for 15 minutes.

[0048] Comparative Example 3

[0049] Prescription (based on 1000mL): gadobutrol 604.72g, colisprofloxacin calcium sodium 513mg, arginine 2.42g, and appropriate amount of tartaric acid.

[0050] Preparation method: Add 90% of the total water volume of the prescription into the dispensing equipment, add the prescribed amount of sodium arginine and calcium benzoate, and stir to dissolve at room temperature; heat the solution to 40-50°C, add the prescribed amount of gadobutrol, stir to dissolve completely and mix thoroughly; after the solution is cooled to room temperature, add tartaric acid to adjust the pH value of the solution to approximately 7.0, and add the remaining prescribed amount of water for injection to the volume; filter the liquid through a 0.22μm sterilizing grade filter cartridge and fill; finally, sterilize at 121°C for 15 minutes.

[0051] Comparative Example 4

[0052] Prescription (based on 1000mL): Gadobutrol 604.72g, Calcobutrol sodium 513mg, arginine 2.42g, and appropriate amount of malic acid.

[0053] Preparation method: Add 90% of the total water volume of the prescription into the liquid dispensing equipment, add the prescribed amount of sodium arginine and calcium benzoate, and stir to dissolve at room temperature; heat the solution to 40-40°C, add the prescribed amount of gadobutrol, stir to dissolve completely and mix thoroughly; after the solution is cooled to room temperature, add malic acid to adjust the pH value of the solution to approximately 7.0, and add the remaining prescribed amount of water for injection to the volume; filter the liquid through a 0.22μm sterilizing grade filter cartridge and fill; finally, sterilize at 121°C for 15 minutes.

[0054] Comparative Example 5

[0055] Prescription (based on 1000mL): 604.72g of gadobutrol, 513mg of colostrum calcium sodium, 2.42g of arginine, and appropriate amount of hydrochloric acid.

[0056] Preparation method: Add 90% of the total water volume of the prescription into the liquid dispensing equipment, add the prescribed amount of sodium arginine and calcium benzoate, and stir to dissolve at room temperature; heat the solution to 40-50°C, add the prescribed amount of gadobutrol, stir to dissolve completely and mix thoroughly; after the solution is cooled to room temperature, add hydrochloric acid to adjust the pH value of the solution to approximately 7.0, and add the remaining prescribed amount of water for injection to the volume; filter the liquid through a 0.22μm sterilizing grade filter cartridge and fill; finally, sterilize at 121°C for 15 minutes.

[0057] Comparative Example 6

[0058] Prescription (based on 1000mL, the composition is consistent with the reference preparation): gadobutrol 604.72g, colisprofloxacin calcium sodium 513mg, tromethamine 1211mg, and appropriate amount of hydrochloric acid.

[0059] Preparation method: Add 90% of the total water volume of the prescription into the liquid dispensing equipment, add the prescribed amount of sodium tromethamine and calcium tromethamine, and stir to dissolve at room temperature; heat the solution to 40-50°C, add the prescribed amount of gadobutrol, stir to dissolve completely and mix thoroughly; after the solution is cooled to room temperature, add hydrochloric acid to adjust the pH value of the solution to approximately 7.0, and add the remaining prescribed amount of water for injection to the volume; filter the liquid through a 0.22μm sterilizing grade filter cartridge and fill; finally, sterilize at 121°C for 15 minutes.

[0060] Product quality testing methods:

[0061] 1. The method for detecting the content of gadobutrol injection according to the present invention:

[0062] Test solution: Accurately measure an appropriate amount of this product and quantitatively dilute it with mobile phase to make a solution containing approximately 1 mg of gadobutrol per 1 mL;

[0063] Reference solution: Take an appropriate amount of gadobutrol reference substance, accurately weigh it, add mobile phase to dissolve it and quantitatively dilute it to make a solution containing approximately 1 mg of gadobutrol per 1 mL.

[0064] Chromatographic conditions: Welch Phenyl-Hexyl (4.6 mm × 25 cm; 3 μm); acetonitrile-water (5:995; v / v), pH adjusted to 3.6 ± 0.1 with 50% (v / v) formic acid in water, as the mobile phase; column temperature, 50°C; flow rate, 1 mL / min; detection wavelength, 195 nm; injection volume, 20 μL.

[0065] 2. The pH detection method of the gadobutrol injection described in the present invention: refer to the pH determination method (General Rule 0631) of the Chinese Pharmacopoeia 2020 edition.

[0066] 3. Detection method of related substances in gadobutrol injection according to the present invention:

[0067] Test solution: Accurately measure an appropriate amount of the product and quantitatively dilute it with mobile phase A to make a solution containing approximately 10 mg of gadobutrol per 1 mL;

[0068] Reference solution: Take an appropriate amount of gadobutrol reference substance, accurately weigh it, dissolve it in mobile phase A, and quantitatively dilute it to make a solution containing approximately 5 μg per 1 mL.

[0069] Chromatographic column: Welch Phenyl-Hexyl (4.6 mm × 25 cm; 3 μm); mobile phase A: acetonitrile-water (5:995; v / v), adjusted to pH 3.6±0.1 with 50% (v / v) formic acid in water; mobile phase B: acetonitrile, gradient elution according to the table below; column temperature: 50°C; flow rate: 1 mL / min; detector: electrospray ionization detector, nebulization temperature: 50°C; injection volume: 20 μL.

[0070]

[0071] 4. Method for detecting free gadolinium in the gadobutrol injection described herein: Accurately measure 20 mL of this product into a 250 mL conical flask, add 30 mL of water, 10 mL of sodium acetate buffer (mix 100 mL of 0.1 mol / L acetic acid with 200 mL of 0.1 mol / L sodium acetate solution; if necessary, adjust the pH to 4.8-5.2 with 0.1 mol / L acetic acid or 0.1 mol / L sodium acetate solution), 1 drop of pyridine, and 10 drops of 0.1% dimethylphenol orange solution. The solution should appear yellow. If it appears red, titrate with 0.001 mol / L disodium ethylenediaminetetraacetic acid solution until the solution changes from red to yellow. Each 1 mL of 0.001 mol / L disodium ethylenediaminetetraacetic acid solution is equivalent to 0.15725 mg of gadolinium.

[0072] Gadobutrol Injection Test Item Limits

[0073]

[0074] Test 1: Comparison of stability before and after sterilization

[0075] Gadobutrol injection samples were tested before and after sterilization to examine changes in properties, pH value, free gadolinium, related substances, and gadobutrol content of the injection before and after sterilization. The test results are shown in Table 1.

[0076] Table 1

[0077]

[0078]

[0079] The results in Table 1 show that the gadobutrol injections prepared in Comparative Examples 1-2, using lysine and histidine as pH buffers, respectively, showed a significant increase in free gadolinium content during sterilization, with the free gadolinium content approaching or exceeding the maximum limit for free gadolinium. The gadobutrol injections prepared in Comparative Examples 3-5, using tartaric acid, malic acid, and hydrochloric acid as pH adjusters, respectively, also experienced a significant increase in free gadolinium content during sterilization, with the free gadolinium content approaching or exceeding the maximum limit for free gadolinium. The gadobutrol injections prepared in Examples 1-6, under the synergistic effect of arginine and citric acid, showed no significant changes in solution properties, pH, free gadolinium, related substances, or gadobutrol content before and after sterilization. The injections had low free gadolinium content and exhibited good stability.

[0080] Test 2: Accelerated test

[0081] The sterilized samples of Examples 1-6 were placed under accelerated conditions (40°C ± 2°C / 75% ± 5%) for 6 months, and then sampled and tested. The properties, pH, free gadolinium, related substances, and gadobutrol contents of the samples were measured and compared to analyze the stability of the samples. The results are shown in Table 2.

[0082] Table 2

[0083]

[0084] The results in Table 2 indicate that the gadobutrol injection samples prepared in Examples 1-6 met all required parameters after 6 months of storage under accelerated conditions, demonstrating long-term stability of the drug solution. Furthermore, the stability of the gadobutrol injection solutions prepared in Examples 1-6 was not significantly different from that of Comparative Example 6, demonstrating comparable stability.

[0085] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that it is still possible to modify the technical solutions described in the aforementioned embodiments, or to make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A gadobutrol injection, characterized in that: The injection comprises the following components: gadobutrol, sodium colbutrol calcium, arginine, a pH regulator and water for injection; the pH regulator makes the pH value of the injection solution be about 6.6-about 8.

0.

2. The injection according to claim 1, characterized in that The pH regulator is selected from one or more of citric acid, phosphoric acid, hydrochloric acid, acetic acid, and tartaric acid.

3. The injection according to claim 1, characterized in that The pH regulator is selected from citric acid, which adjusts the pH value of the injection solution to about 7.0-about 7.

5.

4. The injection according to claim 3, characterized in that Each 1000 mL of injection contains 600-610 g of gadobutrol, 510-515 mg of calcobutrol sodium, 2.0-2.8 g of arginine, an appropriate amount of citric acid, and water for injection; the amount of citric acid is such that the pH value of the injection is adjusted to about 7.0 to about 7.

5.

5. The injection according to claim 4, characterized in that Each 1000 mL of injection contains 604.72 g of gadobutrol, 513 mg of calcobutrol sodium, 2.42 g of arginine, an appropriate amount of citric acid, and water for injection; the amount of citric acid is such that the pH value of the injection is adjusted to about 7.0 to about 7.

5.

6. The method for preparing the injection according to claim 1, characterized in that: The following steps are involved: Step 1: Weigh 80-90% of the prescribed amount of water for injection, add the prescribed amount of colostrum calcium sodium and arginine, and stir to dissolve at room temperature to obtain solution 1; Step 2: Heat Solution 1 to 40-50° C., add the prescribed amount of gadobutrol, and stir to dissolve completely. After the solution is cooled to room temperature, adjust the pH value of the solution to about 6.6-about 8.0 with a pH adjuster to obtain Solution 2; Step 3: Add the remaining amount of water for injection to solution 2 to make up the volume, filter with a microporous membrane, and fill; Step 4: Sterilization and packaging.

7. The preparation method according to claim 6, characterized in that The pH regulator in step 2 is selected from citric acid.

8. The preparation method according to claim 6, characterized in that The pH value of the solution in step 2 is adjusted to about 7.0-about 7.

5.

9. The preparation method according to claim 6, characterized in that The sterilization in step 4 is carried out at 121° C. for 15 min.

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