Ioversol injection and preparation method thereof

Abstract

The invention discloses an ioversol injection and a preparation method thereof, and the preparation method comprises the following steps: dissolving ioversol in first water for injection to obtain a first solution; adding a chelating agent into the first solution for dissolving to obtain a second solution; adding a stabilizer into the second solution for dissolving to obtain a third solution; and adding second injection water into the third solution and / or adjusting the pH value to obtain the liquid medicine. According to the method provided by the invention, the total amount of impurities is effectively reduced, and the stability and quality of the injection are improved.

Description

Technical Field

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

[0002] This section merely provides background information related to the present disclosure and is not necessarily prior art.

[0003] Contrast agents (also known as contrast agents) are chemicals injected (or taken) into human tissues or organs to improve the recognition of images in blood vessels and body cavities during CT scanning. They are one of the most commonly used drugs in interventional radiology operations. Among them, there are many types of iodine contrast agents. Currently, there are more than ten types of iodine contrast agents as diagnostic reagents and are widely used in clinical practice. Among them, loversol, whose chemical name is N,N'-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)hydroxyacetylamino]-2,4,6-triiodo-1,3-benzenedicarbamide, is a new type of triiodine-containing low-osmotic non-ionic contrast agent. After intravascular injection, due to the high iodine content, the X-rays are attenuated, which can make the blood vessels passing through clear until they are diluted. As a non-ionic contrast agent, it is electrically neutral, has low toxicity, high water solubility, low viscosity, low osmotic pressure, low incidence of adverse reactions and relatively low price. It is widely used in clinical practice, including angiography of the adult cardiovascular system; enhanced CT scans of the head and body and intravenous excretory urography; cardiovascular angiography, enhanced CT scans of the head and body and intravenous excretory urography in children. Ioversol 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] According to the properties of the ioversol API, ioversol will undergo a rearrangement reaction in an alkaline aqueous solution environment to generate impurities, and it is also sensitive to light and high temperature, so the existing technical process for preparing ioversol injection requires nitrogen filling protection; in some of the processes, the preparation process also requires the use of activated carbon to decolorize the product. These will undoubtedly reduce production efficiency and increase costs, and there is also a risk of affecting 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 ioversol injection and a preparation method thereof in view of the deficiencies in the prior art.

[0006] In order to solve the above technical problems, the present invention discloses the following technical solutions:

[0007] A method for preparing ioversol injection comprises the following steps:

[0008] (1) dissolving ioversol in first water for injection to obtain a first solution;

[0009] (2) adding calcium sodium edetate to the first solution to dissolve it, thereby obtaining a second solution;

[0010] (3) adding tromethamine to the second solution to dissolve it, thereby obtaining a third solution;

[0011] (4) adding the second water for injection and adjusting the pH of the obtained third solution to obtain a drug solution;

[0012] (5) The liquid medicine is filtered, sealed and sterilized to obtain ioversesol injection.

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

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

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

[0016] Wherein, the mass ratio of ioversol, 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, part of the second water for injection is first added to 85%-95% of the total amount of the first water for injection and the second water for injection, and the remaining second water for injection is added after adjusting the pH; preferably, part of the second water for injection is first added to 85%-95% of the total amount of the first water for injection and the second water for injection, then cooled to room temperature, and the remaining second water for injection is added to make up the volume after adjusting the pH; preferably, part of the second water for injection is first added to 90% of the total amount of the first water for injection and the second water for injection, then cooled to room temperature, and the remaining second water for injection is added to make up the volume after adjusting the pH.

[0018] In step (4), the pH is 6.7-6.9, preferably 6.8; preferably, the pH is adjusted using 0.5-1.5 mol / L hydrochloric acid, preferably 1 mol / L hydrochloric acid; the preparation method of 1 mol / L hydrochloric acid is: 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 0.12-0.32 μm filter membrane, sealed, and sterilized to obtain the ioversol injection solution. The drug solution is preferably filtered through a 0.22 μm filter membrane, sealed, and sterilized to obtain the ioversol injection solution.

[0020] Wherein, the filter membrane is preferably an aqueous phase filter membrane.

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

[0022] The ioversol injection prepared by the above method is also within the protection scope of the present invention.

[0023] The invention provides a method for preparing a stable ioversol injection, which can effectively reduce the amount of impurities and improve the stability and quality of the injection by controlling the raw materials, the order of feeding, the pH value of the solution, etc., and obtain an ioversol injection with good stability and low impurity content.

[0024] The invention has a simple preparation process, does not need to add activated carbon for decolorization after liquid preparation, does not need to fill with nitrogen during liquid preparation and potting, and is easy for industrial scale-up production.

[0025] Beneficial effects:

[0026] 1. The ioversol injection is prepared by adding the raw materials first and then the excipients. While maintaining the stability of the injection, the content of related impurities in the injection is low, avoiding the influence of nitrogen filling process and activated carbon decolorization on the quality of the ioversol injection product.

[0027] 2. During the stability study, the quality stability of the ioversol injection of the present application was better than that of the reference preparation and had higher stability.

[0028] 3. The ioversol injection of this application has stable quality and can replace original research drugs in clinical practice, saving medical expenses. At the same time, it improves the quality of generic drugs and the overall development level of the pharmaceutical industry, ensuring the safety and effectiveness of public drug use. DETAILED DESCRIPTION

[0029] The present invention will be further described in detail below in conjunction with specific embodiments, and the above and / or other advantages of the present invention will become clearer. However, it is easy for those skilled in the art to understand that the contents described in the embodiments are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

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

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

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

[0033] The detection methods of the related substances in the following embodiments are as follows:

[0034] Test solution: Take an appropriate amount of the product and dilute with water to make a solution containing about 1 mg per 1 ml.

[0035] Control solution: Accurately measure an appropriate amount of the test solution and quantitatively dilute it with water to make a solution containing approximately 10 μg per 1 ml.

[0036] Reference solution: Take appropriate amounts of impurity I reference substance and impurity II reference substance, weigh accurately, dissolve in water and quantitatively dilute to make a solution containing approximately 1 μg of impurity I and 5 μg of impurity II per 1 ml.

[0037] Take equal volumes of system suitability solution and reference solution respectively and mix them.

[0038] Chromatographic conditions: octylsilane bonded silica gel as filler; acetonitrile-water (4:96) as mobile phase; detection wavelength at 254 nm; injection volume 20 μl.

[0039] Determination method: Accurately measure the test solution, control solution and reference substance solution, inject them into the liquid chromatograph respectively, and record the chromatogram of the test solution to 3.5 times the retention time of the main component peak. Calculate the impurities I and II by peak area according to the external standard method; other single impurities are calculated by self-control method.

[0040] Example 1

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

[0042] Table 1 Injection prescription

[0043] name Per 100ml Ioversol 74.1g Edetate calcium sodium 0.02g Tromethamine 0.36g hydrochloric acid Moderate Water for injection Add to 100ml

[0044] Preparation method:

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

[0046] (2) Add the prescribed amount of edetate calcium sodium 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 and stir evenly to obtain the drug solution.

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

[0052] Comparative Example 1: Different addition orders of API, chelating agent and stabilizer

[0053] Comparative Example 1-1

[0054] The difference from Example 1 is that when preparing the solution, ioversol is added first, then tromethamine is added, and finally calcium sodium edetate is added.

[0055] Comparative Example 1-2

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

[0057] Comparative Examples 1-3

[0058] The difference from Example 1 is that when preparing the solution, calcium sodium edetate is added first, then ioversol is added, and finally tromethamine is added.

[0059] Comparative Examples 1-4

[0060] The difference from Example 1 is that when preparing the solution, tromethamine is added first, then ioversol is added, and finally edetate calcium sodium is added.

[0061] Comparative Examples 1-5

[0062] The difference from Example 1 is that step (2) and step (3) are combined into one step during the preparation of the solution, that is, after adding the prescribed amount of ioversol, calcium sodium edetate and tromethamine are added simultaneously.

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

[0064] Table 2 Related substances / %

[0065]

[0066] From the results in the above table, it can be seen that compared with Comparative Example 1, the iodine impurity II and the total impurities in Example 1 are both the smallest.

[0067] Comparative Example 2: Change the temperature of the injection water in step 1

[0068] Comparative Example 2-1

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

[0070] Comparative Example 2-2

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

[0072] Comparative Example 2-3

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

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

[0075] Table 3

[0076]

[0077] From the results in the above table, it can be seen that the total impurities of Example 1 and Comparative Example 2-1 are basically the same, and are lower than those of Comparative Example 2-2 and Comparative Example 2-3. Considering that the concentration of the raw material contained in the unit dosage injection is high, the solubility of the raw material is poor at 50°C, the dissolution rate is slow, and some raw materials cannot be dissolved, so 60°C is selected as the liquid preparation temperature.

[0078] Comparative Example 3: Changing Sterilization Parameters

[0079] Comparative Example 3-1

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

[0081] Comparative Example 3-2

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

[0083] Comparative Example 3-3

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

[0085] Comparative Examples 3-4

[0086] The difference from Example 1 is that step 7 is 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] From the results in the above table, it can be seen that the F0 values ​​of Example 1, Comparative Example 3-3 and Comparative Example 3-4 can all reach more than 12. There is no significant difference in the total impurities between Example 1 and Comparative Example 3-3. Compared with Comparative Example 3-4, the total impurities of Example 1 are lower. According to the sterilization decision tree and the requirements of the "Guidelines for Research and Validation of Sterilization and Aseptic Process for Chemical Injections (Trial)", the overkilling method is preferred. Therefore, the sterilization conditions of Example 1 can meet the conventional sterilization requirements.

[0091] Comparative Example 4: Changing pH

[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 of each comparative example are shown in Table 5.

[0097] Table 5

[0098]

[0099] From the above results, it can be seen that compared with Comparative Example 4, the iodine impurity II, the maximum unknown single impurity and the total impurities in Example 1 are all lower.

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

[0101] Comparative Example 5-1

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

[0103] Comparative Example 5-2

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

[0105] The results of each comparative example are shown in Table 6.

[0106] Table 6

[0107]

[0108] From the above results, it can be seen that compared with Comparative Example 5, Example 1 has lower impurities II, maximum unknown single impurities and total impurities in ioversenol, which proves that calcium sodium edetate and tromethamine have better quality protection effects on injections.

[0109] Example 2 Stability Study

[0110] The stability of the ioversol injection prepared in Example 1 and a reference preparation (trade name: Optiray 350; dosage form: injection; source: the United States) was investigated, and the investigation indexes included pH value, color, related substances and content of the liquid. The results are shown in Table 7.

[0111] Table 7

[0112]

[0113] From the above results, it can be seen that compared with the reference preparation, the ioversol injection prepared in Example 1 has better stability in pH, related substances, solution color and content within 30 days of the influencing factors.

[0114] Comparative Example 6

[0115] Same as Example 1, except that the content of auxiliary materials 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] From the above results, it can be seen that compared with comparative examples 6-1 to 6-4, Example 1 has lower levels of iodine impurity I, iodine impurity II, maximum unknown single impurity and total impurities. It can be seen that only at a specific excipient content can the related substances of iodine injection remain stable.

[0122] The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A method for preparing ioversol injection, characterized in that: The following steps are involved: Dissolving ioversol in first water for injection to obtain a first solution; Adding calcium sodium edetate to the first solution to dissolve it, thereby obtaining a second solution; adding tromethamine to the second solution to dissolve it, thereby obtaining a third solution; The obtained third solution is added with the second water for injection and the pH is adjusted to obtain a drug solution.

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

3. The preparation method according to claim 1, characterized in that: The temperature of the first injection water is 50°C-80°C, preferably 48°C-65°C, preferably 50°C-60°C.

4. The preparation method according to claim 1, characterized in that: The mass volume ratio of the ioversol to the first water for injection is 0.8-1.6 g / mL, preferably 1.0-1.4 g / mL, and preferably 1.2 g / mL.

5. The preparation method according to claim 1, characterized in that: The mass ratio of ioversol, 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.

6. The preparation method according to claim 1, characterized in that: The second water for injection is added twice; preferably, part of the second water for injection is first added to 85%-95% of the total amount of the first water for injection and the second water for injection, and the remaining water for injection is added after the pH is adjusted; preferably, part of the second water for injection is first added to 85%-95% of the total amount of the first water for injection and the second water for injection, then cooled to room temperature, and the remaining water for injection is added after the pH is adjusted.

7. The preparation method according to claim 1 or 6, characterized in that: 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.

8. The preparation method according to claim 1, characterized in that: The drug solution is filtered through a 0.12-0.32 μm filter membrane, sealed, and sterilized to obtain the ioversol injection solution. The drug solution is preferably filtered through a 0.22 μm filter membrane, sealed, and sterilized to obtain the ioversol injection solution.

9. The preparation method according to claim 8, characterized in that: The sterilization temperature is 119-123°C, preferably 120-122°C, preferably 121°C; preferably, the sterilization time is 10-17 min, preferably 12-15 min.

10. Ioversol injection prepared by the method according to any one of claims 1 to 9.

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