Iodipamide injection and a method for preparing the same

Abstract

The application discloses iodine ioversol injection and a preparation method thereof. The preparation method comprises the following steps: dissolving iodine ioversol in first water for injection to obtain a first solution; adding a chelating agent into the first solution to obtain a second solution; adding a stabilizer into the second solution to obtain a third solution; and adding second water for injection and / or adjusting pH of the third solution to obtain a medicine solution. The method provided by the application effectively reduces the total amount of impurities, and improves the stability and quality of the injection.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to an iodofol injection and its preparation method. Background Technology

[0002] This section provides only background information relevant to this disclosure and is not necessarily prior art.

[0003] Contrast agents (also known as contrast agents) are chemical products injected (or ingested) into human tissues or organs during CT scans to improve the clarity of images observed in blood vessels and body cavities. They are among the most commonly used drugs in interventional radiology procedures. Iodine contrast agents are diverse, with more than ten types currently used as diagnostic reagents in clinical practice. Among them, loversol, chemically named N,N'-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)hydroxyacetamido]-2,4,6-triiodo-1,3-phenylenediamide, is a novel triiodine-containing hypotonic nonionic contrast agent. After intravascular injection, its high iodine content attenuates X-rays, allowing for clear imaging of the blood vessels it passes through until it is diluted. As a non-ionic contrast agent, it possesses advantages such as electrical neutrality, low toxicity, high water solubility, low viscosity, low osmotic pressure, low incidence of adverse reactions, and relatively low price. It is widely used clinically, including in angiography of the adult cardiovascular system; enhanced CT scans of the head and body and intravenous urography; and cardiovascular angiography, enhanced CT scans of the head and body and intravenous urography in children. Ioflufenicol injection was developed by Liebel-Flarsheim Canada Inc. / Guerbet and was first approved for marketing in the United States on December 30, 1988, in the European Union on December 30, 1989, and in China on March 2, 1999.

[0004] Based on the properties of iodofol raw material, iodofol undergoes a rearrangement reaction in an alkaline aqueous solution, generating impurities. It is also sensitive to light and high temperatures. Therefore, existing technologies for preparing iodofol injection require nitrogen purging for protection. Some processes also require the use of activated carbon for decolorization. These factors undoubtedly reduce production efficiency, increase costs, and pose a risk to product quality. Summary of the Invention

[0005] Purpose of the invention: The technical problem to be solved by the present invention is to provide a stable iodofol injection solution and its preparation method, in order to address the shortcomings of the prior art.

[0006] To solve the above-mentioned technical problems, the present invention discloses the following technical solution:

[0007] A method for preparing iodofol injection includes the following steps:

[0008] (1) Dissolve iodofol in the first water for injection to obtain the first solution;

[0009] (2) Add calcium sodium edetate to the first solution to dissolve it, and obtain the second solution;

[0010] (3) Add tromethamine to the second solution to dissolve it, and obtain the third solution;

[0011] (4) The obtained third solution was mixed with second water for injection and the pH was adjusted to obtain the drug solution;

[0012] (5) The drug solution is filtered, filled and sterilized to obtain iodofol injection.

[0013] In step (1), the particle size D90 of the iodofol is 70-170μm, such as 80μm, 90μm, 100μm, 130μm, or 150μm.

[0014] In step (1), the temperature of the first water for injection is 50℃-80℃, preferably 48℃-65℃, and more preferably 50℃-60℃.

[0015] In step (1), the mass-to-volume ratio of iodofol to the first water for injection is 0.8-1.6 g / mL, preferably 1.0-1.4 g / mL, and more preferably 1.2 g / mL.

[0016] The mass ratio of iodofol, calcium sodium edetate, tromethamine, and water for injection is 74.1:(0.015-0.025):(0.35-0.37):(98-102), preferably 74.1:0.02:0.36:100.

[0017] In step (4), the second water for injection is added twice; preferably, a portion of the second water for injection is added first to 85%-95% of the total amount of the first and second water for injection, and the pH is adjusted before adding the remaining second water for injection; preferably, a portion of the second water for injection is added first to 85%-95% of the total amount of the first and second water for injection, then cooled to room temperature, the pH is adjusted before adding the remaining second water for injection to make up the volume; preferably, a portion of the second water for injection is added first to 90% of the total amount of the first and second water for injection, then cooled to room temperature, the pH is adjusted before adding the remaining second water for injection to make up the volume.

[0018] In step (4), the pH is 6.7-6.9, preferably 6.8; preferably, the pH is adjusted with 0.5-1.5 mol / L hydrochloric acid, preferably with 1 mol / L hydrochloric acid; the preparation method of the 1 mol / L hydrochloric acid is as follows: measure 8.3 ml of concentrated hydrochloric acid and add it to 100 ml of water for injection.

[0019] In step (5), the drug solution is filtered through a 0.12-0.32μm filter membrane, filled, and sterilized to obtain iodofol injection solution. Preferably, the drug solution is filtered through a 0.22μm filter membrane, filled, and sterilized to obtain iodofol injection solution.

[0020] The filter membrane is preferably an aqueous phase filter membrane.

[0021] In step (5), the sterilization temperature is 106-126℃, preferably 108-124℃, and preferably 121℃; preferably, the sterilization time is 12-30min, such as 12min, 15min, or 20min.

[0022] Ioflufenicol injection prepared by the above method is also within the scope of protection of this invention.

[0023] The present invention provides a stable method for preparing iodofol injection, which can effectively reduce impurities and improve the stability and quality of the injection by controlling the raw materials, the order of feeding, and the pH value of the solution, thus obtaining iodofol injection with good stability and low content of related impurities.

[0024] The preparation process of this invention is simple, no activated carbon is needed for decolorization after solution preparation, and no nitrogen purging is required during solution preparation and filling, making it easy to scale up for industrial production.

[0025] Beneficial effects:

[0026] 1. Ioflufenicol injection is prepared by first adding the active pharmaceutical ingredient (API) and then the excipients. This ensures the stability of the injection while keeping the content of impurities low, thus avoiding the impact of nitrogen filling and activated carbon decolorization on the product quality of ioflufenicol injection.

[0027] 2. The iodofol injection of this application exhibits better quality stability than the reference preparation during the stability study, demonstrating high stability.

[0028] 3. The iodofol injection of this application has stable quality, can replace the original drug in clinical practice, save medical expenses, improve the quality of generic drugs and the overall development level of the pharmaceutical industry, and ensure the safety and effectiveness of public medication. Detailed Implementation

[0029] The present invention will be further described in detail below with reference to specific embodiments, and the advantages of the present invention in the above and / or other aspects will become clearer. However, those skilled in the art will readily understand that the description of the embodiments is for illustrative purposes only and should not, and will not, limit the present invention as described in detail in the claims.

[0030] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; unless otherwise specified, the reagents and materials are commercially available.

[0031] The iodofol impurity I and iodofol impurity II described in the following examples are as shown in the iodofol section of Part II of the Chinese Pharmacopoeia 2015 edition.

[0032] The particle size D90 of the iodofol described in the following examples is 80 μm.

[0033] The detection methods for the substances in the following examples are as follows:

[0034] Test solution: Take an appropriate amount of this product and dilute it with water to prepare a solution containing approximately 1 mg per 1 ml.

[0035] Accurately measure an appropriate amount of the test solution and dilute it quantitatively with water to prepare a solution containing approximately 10 μg per ml.

[0036] To prepare the reference solution, take appropriate amounts of impurity I reference standard and impurity II reference standard, accurately weigh them, dissolve them in water, and quantitatively dilute them to prepare a solution containing approximately 1 μg of impurity I and 5 μg of impurity II per 1 ml.

[0037] For system suitability testing, measure equal volumes of the reference solution and the control solution separately, and mix them thoroughly.

[0038] The chromatographic conditions were as follows: octylsilane-bonded silica gel was used as the stationary phase; acetonitrile-water (4:96) was used as the mobile phase; the detection wavelength was 254 nm; and the injection volume was 20 μl.

[0039] For the assay, accurately measure the test solution, control solution, and reference standard solution, and inject them separately into the liquid chromatograph. Record the chromatogram of the test solution up to 3.5 times the retention time of the main component peak. Calculate the results for impurities I and II based on peak area using the external standard method; other individual impurities are calculated using the self-reference method.

[0040] Example 1

[0041] This embodiment is prepared according to the following prescription ratio:

[0042] Table 1. Injection Prescription Table

[0043] Iodophorol 74.1g Sodium edetate 0.02g Tromethamine 0.36g hydrochloric acid Appropriate amount Water for Injection Add to 100ml

[0044] Preparation method:

[0045] (1) Take 60 ml of water for injection, keep warm to 60°C, add the prescribed amount of iodofol, and stir until fully dissolved.

[0046] (2) Add the prescribed amount of sodium edetate and stir until fully dissolved.

[0047] (3) Add the prescribed amount of tromethamine and stir until fully dissolved.

[0048] (4) Add water for injection to make up to 90% of the total amount of water for injection, and then cool to room temperature.

[0049] (5) Adjust the pH to 6.8 with 1 mol / L hydrochloric acid.

[0050] (6) Add water for injection to the final volume, stir well, and obtain the drug solution.

[0051] (7) The drug solution is filtered through a 0.22μm aqueous phase filter membrane, filled and sterilized at 121℃ for 15 minutes to prepare an iodophor injection solution.

[0052] Comparative Example 1: The active pharmaceutical ingredient, chelating agent, and stabilizer were added in a different order.

[0053] Comparative Example 1-1

[0054] The difference from Example 1 is that when preparing the solution, iodofol is added first, followed by tromethorphan, and finally sodium edetate.

[0055] Comparative Examples 1-2

[0056] The difference from Example 1 is that when preparing the solution, tromethamine is added first, followed by calcium sodium edetate, and finally iodofol is added.

[0057] Comparative Examples 1-3

[0058] The difference from Example 1 is that calcium sodium edetate is added first, followed by iodofol, and finally tromethamine.

[0059] Comparative Examples 1-4

[0060] The difference from Example 1 is that when preparing the solution, tromethamine is added first, followed by iodofol, and finally sodium edetate.

[0061] Comparative Examples 1-5

[0062] The difference from Example 1 is that steps (2) and (3) are combined into one step when preparing the solution, that is, after adding the prescribed amount of iodofol, calcium sodium edetate and tromethamine are added at the same time.

[0063] The test results of related substances in the injection solutions obtained by different raw material and auxiliary material feeding sequences are shown in Table 2.

[0064] Table 2 Related substances / %

[0065]

[0066] The results in the table above show that, compared to Comparative Example 1, the iodophor impurity II and total impurities in Example 1 are the smallest.

[0067] Comparative Example 2: Change step 1 by adjusting the temperature of the water for injection.

[0068] Comparative Example 2-1

[0069] The difference from Example 1 is that in step 1, the water for injection is kept warm to 50°C.

[0070] Comparative Example 2-2

[0071] The difference from Example 1 is that in step 1, the water for injection is kept warm to 70°C.

[0072] Comparative Examples 2-3

[0073] The difference from Example 1 is that in step 1, the water for injection is kept warm to 80°C.

[0074] The results of the detection of related substances in the injection solutions obtained at different solution preparation temperatures are shown in Table 3.

[0075] Table 3

[0076]

[0077] The results in the table above show that the total impurities in Example 1 and Comparative Example 2-1 are basically the same, and are lower than those in Comparative Examples 2-2 and 2-3. Considering that the concentration of the active pharmaceutical ingredient in the unit volume of injection is relatively high, the solubility of the active pharmaceutical ingredient is poor at 50°C, the dissolution rate is slow, and some active pharmaceutical ingredient cannot be dissolved, therefore 60°C was selected as the solution preparation temperature.

[0078] Comparative Example 3: Changing Sterilization Parameters

[0079] Comparative Example 3-1

[0080] The difference from Example 1 is that sterilization was not performed in step 7.

[0081] Comparative Example 3-2

[0082] The difference from Example 1 is that step 7 involves sterilization at 115°C for 30 minutes.

[0083] Comparative Examples 3-3

[0084] The difference from Example 1 is that step 7 involves sterilization at 121°C for 12 minutes.

[0085] Comparative Examples 3-4

[0086] The difference from Example 1 is that step 7 involves sterilization at 121°C for 30 minutes.

[0087] The results of the sterilization condition investigation are shown in Table 4.

[0088] Table 4

[0089]

[0090] The results in the table above show that the F0 values ​​of Example 1 and Comparative Examples 3-3 and 3-4 are all above 12. There is no significant difference in total impurities between Example 1 and Comparative Examples 3-3, but Example 1 has lower total impurities compared to Comparative Examples 3-4. Based on the sterilization decision tree and the requirements of the "Guiding Principles for Research and Validation of Sterilization and Aseptic Processes for Chemical Injectables (Trial Implementation)," the overkill method is preferred. Therefore, the sterilization conditions of Example 1 can meet the requirements of conventional sterilization.

[0091] Comparative Example 4: Changing pH value

[0092] Comparative Example 4-1

[0093] The difference from Example 1 is that step 5 adjusts the pH to 7.0.

[0094] Comparative Example 4-2

[0095] The difference from Example 1 is that step 5 adjusts the pH to 7.4.

[0096] The results for each pair of proportions are shown in Table 5.

[0097] Table 5

[0098]

[0099] The results above show that, compared with Comparative Example 4, the levels of iodophor impurity II, maximum unknown single impurity, and total impurities are all lower in Example 1.

[0100] Comparative Example 5: Chelating agents and stabilizers of different components

[0101] Comparative Example 5-1

[0102] The difference from Example 1 is that calcium sodium edetate is replaced with disodium edetate.

[0103] Comparative Example 5-2

[0104] The difference from Example 1 is that tromethamine is replaced with sodium sulfite.

[0105] The results for each pair of proportions are shown in Table 6.

[0106] Table 6

[0107]

[0108] The results above show that, compared with Comparative Example 5, Example 1 has lower levels of iodofol impurity II, maximum unknown single impurity, and total impurities, demonstrating that calcium sodium edetate and tromethamine have better quality protection effects on the injection.

[0109] Example 2 Stability Study

[0110] The stability of the iodofol injection prepared in Example 1 was studied against a reference formulation (trade name: Optiray 350; dosage form: injection; source: USA). The evaluation parameters included pH value, color, related substances, and content of the solution. The results are shown in Table 7.

[0111] Table 7

[0112]

[0113] The results above show that, compared with the reference preparation, the iodofol injection prepared in Example 1 has better stability in terms of pH, related substances, solution color and content within 30 days under influencing factors.

[0114] Comparative Example 6

[0115] Same as Example 1, except that the content of excipients is changed, as shown in Table 8 below.

[0116] Table 8

[0117]

[0118] The results are shown in Table 9.

[0119] Table 9

[0120]

[0121] The results above show that, compared to comparative examples 6-1 to 6-4, Example 1 has lower levels of iodofol impurity I, iodofol impurity II, maximum unknown single impurity, and total impurities. This indicates that the related substances in iodofol injection can only remain stable at specific excipient contents.

[0122] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

Claims

1. A method for preparing iodofol injection, characterized in that, Includes the following steps: Ioflucanol was dissolved in first injection water at 60°C to obtain the first solution; Calcium sodium edetate is added to the first solution to dissolve it, thus obtaining the second solution; tromethamine is added to the second solution to dissolve it, thus obtaining the third solution; the third solution is then supplemented with second water for injection to bring it to 90% of the total volume of water for injection and the pH is adjusted to 6.7-6.9 to obtain the drug solution; the drug solution is filtered through a 0.22μm filter membrane, filled, and sterilized at 121℃ for 12-30 min to obtain iodofol injection solution; The pH is adjusted using 1 mol / L hydrochloric acid; The second water for injection is prepared by first adding a portion of the second water for injection to 90% of the total amount of the first and second water for injection, then cooling it to room temperature, adjusting the pH to 6.7-6.9, and then adding the remaining water for injection. The mass ratio of iodofol, calcium sodium edetate, tromethamine, and water for injection is 74.1:0.02:0.36:

100.

2. The preparation method according to claim 1, characterized in that, The particle size D90 of the iodofol is 70-170 μm.

3. The preparation method according to claim 1, characterized in that, The mass-to-volume ratio of iodofol to the first water for injection is 0.8-1.6 g / mL.

4. The preparation method according to claim 1, characterized in that, The mass-to-volume ratio of iodofol to the first water for injection is 1.0-1.4 g / mL.

5. The preparation method according to claim 1, characterized in that, The mass-to-volume ratio of iodofol to the first water for injection is 1.2 g / mL.

6. The preparation method according to claim 1, characterized in that, The pH value is 6.

8.

7. The preparation method according to claim 1, characterized in that, The sterilization time is 12-15 minutes.

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