Multi-trace element injection and preparation method thereof

Abstract

The invention belongs to the field of pharmaceutical preparations, and relates to a multi-trace element injection and a preparation method thereof. The multi-trace element injection comprises effective components, a stabilizer and water, the effective components comprise chromium chloride, copper chloride, ferric chloride, manganese chloride, sodium molybdate, sodium selenite, zinc chloride, potassium iodide and sodium fluoride, and the stabilizer comprises xylitol, a pH regulator and an additive; and the additive is PEG (Polyethylene Glycol) 400 or PEG 600. The multi-trace element injection provided by the invention can effectively inhibit the loss of iodine in the sterilization process, and the stability, economical efficiency and production controllability of the multi-trace element injection are fundamentally improved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations and relates to a multi-trace element injection solution and its preparation method. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Multi-element injection (III) is a compound preparation containing trace elements such as selenium, iron, zinc, copper, manganese, iodine, molybdenum, chromium, cobalt, and fluorine, meeting the basic and moderate trace element needs of patients during intravenous nutrition. Currently, multi-element injections (III) marketed domestically and internationally generally use xylitol or sorbitol as stabilizers in their formulations and adjust the pH with hydrochloric acid. However, this preparation faces the technical challenge of iodine loss during the final high-temperature sterilization process. According to the original product's market review report, the product needs to be sterilized at temperatures above 120°C (e.g., 121°C). During this high-temperature process, potassium iodide will generate elemental iodine (I2) and sublimate, resulting in an irreversible decrease in its content. To compensate for this loss and ensure that the iodine content in the finished product meets the standards, current processes all adopt a solution of pre-adding an excess of 20% potassium iodide.

[0004] While overfeeding can guarantee the final content, it is essentially a post-hoc compensation for losses rather than a fundamental improvement in product stability. It has inherent drawbacks such as increasing raw material costs and potential quality fluctuation risks. Therefore, there is an urgent need to develop a new technology that can effectively inhibit or reduce the loss of iodine during sterilization. Summary of the Invention

[0005] To address the shortcomings of existing technologies, the purpose of this invention is to provide a multi-trace element injection solution and its preparation method. The multi-trace element injection solution provided by this invention can effectively inhibit the loss of iodine during sterilization, fundamentally improving the stability, economy, and production controllability of the product.

[0006] To achieve the above objectives, the technical solution of the present invention is as follows: In a first aspect, a multi-trace element injection solution includes an active ingredient, a stabilizer, and water. The active ingredient includes chromium chloride, copper chloride, ferric chloride, manganese chloride, sodium molybdate, sodium selenite, zinc chloride, potassium iodide, and sodium fluoride. The stabilizer includes xylitol, a pH adjuster, and an additive. The additive is PEG400 or PEG600.

[0007] This invention demonstrates that adding PEG400 or PEG600 to a multi-trace element injection (III) can significantly reduce iodine loss during sterilization; experiments show that the iodine loss rate can be reduced from 20% to below 9%. PEG400 exhibits a more effective inhibition of iodine loss during sterilization.

[0008] Meanwhile, the multi-trace element injection solution described in the first aspect of this invention can achieve the above-mentioned objective by using the existing multi-trace element injection solution (III) preparation method and adding additives along with xylitol. Further research by this invention has found that improvements to the preparation method can further reduce iodine loss during sterilization. Therefore, in another aspect, this invention provides a method for preparing a multi-trace element injection solution, wherein the raw material composition of the multi-trace element injection solution is the same as that of the multi-trace element injection solution in the first aspect of this invention, comprising the following steps: Dissolve xylitol in water, then add chromium chloride, copper chloride, ferric chloride, manganese chloride, sodium molybdate, sodium selenite, zinc chloride, and sodium fluoride and mix well. Then adjust the pH of the solution to the set value using a pH adjuster to obtain solution 1. Dissolve the additive in water, then adjust the pH of the solution to the set value using a pH adjuster, and then add potassium iodide to dissolve completely to obtain solution 2; Mix solution 1 and solution 2, add water, and filter to obtain the final product.

[0009] Experiments show that the preparation method of the present invention can further reduce the loss of iodine during sterilization, and the iodine loss rate can be further reduced to below 2%.

[0010] The beneficial effects of this invention are as follows: 1. The various trace element injection solutions provided by this invention effectively inhibit the generation or sublimation of elemental iodine (I2) from the source by adding PEG400 or PEG600, reducing the iodine loss rate by an order of magnitude (from the original 20% to below 9%), achieving active stabilization of iodine, and enabling the product to maintain extremely high content consistency after high-temperature sterilization.

[0011] 2. The preparation method provided by this invention involves taking PEG400 or PEG600 and potassium iodide out of the formulation system and mixing and dissolving them, while adjusting their addition order. This further reduces the iodine loss rate during high-temperature sterilization, which can be as low as below 2%. This not only reduces the process complexity caused by compensation uncertainties in the production process, but also makes the amount of feed closer to the theoretical finished product content, making the process more controllable and precise. It reduces the risk of batch-to-batch quality differences caused by feed calculation deviations or process fluctuations, which is conducive to improving the uniformity and reliability of product quality. Attached Figure Description

[0012] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0013] Figure 1 The curves show the iodine loss rate of the various trace element injection solutions (Ⅲ) prepared in Examples 4, 6-8 of this invention after sterilization. Detailed Implementation

[0014] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0015] It should be noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of exemplary embodiments according to the invention. As used herein, the singular form is intended to include the plural form as well, unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0016] In view of the problem of excessive iodine loss during the sterilization process of multi-trace element injection (III), in order to solve the above-mentioned technical problem, the present invention proposes a multi-trace element injection and its preparation method.

[0017] Various trace element injection solutions were prepared according to the original formulation. After sterilization at 121℃ for 15 min, the iodine loss rate of the samples was 20.4%, indicating that iodine loss could not be avoided during sterilization of the products prepared according to the original formulation. By preparing products containing propylene glycol, PEG300, PEG400, or PEG600, the iodine loss rate before and after sterilization at 121℃ for 15 min was improved compared to the original formulation. The iodine loss rates of the products containing PEG400 and PEG600 were 6.8% and 7.2%, respectively. To further investigate the iodine loss rate before and after sterilization, products containing different amounts of PEG400 were prepared. It was found that when the PEG400 concentration was 1.4 mg / ml to 2.1 mg / ml, the iodine loss rate after sterilization was 5.8% to 6.3% after sterilization at 121℃ for 15 min. Based on these research results, the technical solution for the various trace element injection solutions of this invention is proposed.

[0018] A typical embodiment of the present invention provides a multi-trace element injection solution, comprising active ingredients, stabilizers, and water. The active ingredients include chromium chloride, copper chloride, ferric chloride, manganese chloride, sodium molybdate, sodium selenite, zinc chloride, potassium iodide, and sodium fluoride. The stabilizers include xylitol, pH adjusters, and additives; the additives are PEG400 or PEG600.

[0019] In some embodiments, the mass of the additive per milliliter of water is 0.5 to 3.0 g. Specifically, the mass of the additive per milliliter of water is 0.7 to 2.8 g. When the mass of the additive per milliliter of water is 1.3 to 1.5 g, the inhibition effect on iodine loss during sterilization is better.

[0020] The pH adjuster is used to adjust the pH of the multi-trace element injection solution. In some embodiments, the pH of the multi-trace element injection solution is 2.4~2.5. Specifically, the pH adjuster is generally an acid, such as hydrochloric acid, nitric acid, sulfuric acid, etc. Hydrochloric acid is preferred in this invention, and more specifically, the concentration of hydrochloric acid is 0.9~1.1 mol / L. The unit mol / L can be abbreviated as M.

[0021] In some embodiments, the mass of xylitol per milliliter of water is 0.25 to 0.35 g.

[0022] In some embodiments, the molar content of the active ingredients per milliliter of water is as follows: chromium chloride 0.015~0.025 μmol, copper chloride 0.50~0.70 μmol, ferric chloride 1.5~2.5 μmol, manganese chloride 0.05~0.15 μmol, sodium molybdate 0.015~0.025 μmol, sodium selenite 0.05~0.15 μmol, zinc chloride 7.0~8.5 μmol, potassium iodide 0.015~0.025 μmol, and sodium fluoride 4.5~5.5 μmol.

[0023] In some embodiments, the molar content of the active ingredients per milliliter of water is as follows: chromium chloride 0.018~0.022 μmol, copper chloride 0.55~0.65 μmol, ferric chloride 1.8~2.2 μmol, manganese chloride 0.08~0.12 μmol, sodium molybdate 0.018~0.022 μmol, sodium selenite 0.08~0.12 μmol, zinc chloride 7.5~8.0 μmol, potassium iodide 0.018~0.022 μmol, and sodium fluoride 4.8~5.2 μmol.

[0024] In some embodiments, the molar amounts of the active ingredients per milliliter of water are as follows: chromium chloride 0.019~0.021 μmol, copper chloride 0.59~0.61 μmol, ferric chloride 1.9~2.1 μmol, manganese chloride 0.09~0.11 μmol, sodium molybdate 0.019~0.021 μmol, sodium selenite 0.09~0.11 μmol, zinc chloride 7.6~7.8 μmol, potassium iodide 0.019~0.021 μmol, and sodium fluoride 4.9~5.1 μmol.

[0025] Another embodiment of the present invention provides a method for preparing a multi-trace element injection solution, wherein the raw material composition of the multi-trace element injection solution is the same as that of the above-mentioned multi-trace element injection solutions, and includes the following steps: Dissolve xylitol in water, then add chromium chloride, copper chloride, ferric chloride, manganese chloride, sodium molybdate, sodium selenite, zinc chloride, and sodium fluoride and mix well. Then adjust the pH of the solution to the set value using a pH adjuster to obtain solution 1. Dissolve the additive in water, then adjust the pH of the solution to the set value using a pH adjuster, and then add potassium iodide to dissolve completely to obtain solution 2; Mix solution 1 and solution 2, add water, and filter to obtain the final product.

[0026] Based on the fact that adding PEG400 or PEG600 can greatly reduce the iodine loss rate of products during high-temperature sterilization, this invention further studies the effect of preparation method on the iodine loss rate of products during high-temperature sterilization. The experiment found that only the above preparation method can further reduce the iodine loss rate of products during high-temperature sterilization, with the iodine loss rate not exceeding 2%, thereby avoiding excessive feeding during the production process to ensure iodine content.

[0027] In some embodiments, xylitol is dissolved in 45-55% of the prescribed amount of water. Under these conditions, the xylitol dissolves better, which is beneficial for the subsequent dissolution of the active ingredients.

[0028] In some embodiments, the water temperature for dissolving xylitol is 20–40°C. This temperature condition is more conducive to the dissolution of the prescribed amount of xylitol.

[0029] In some embodiments, the pH value of solution 1 is 2.4 to 2.5.

[0030] In some embodiments, a water-soluble additive at a dosage of 15-25% is used. Under these conditions, the dissolution effect of the prescribed dosage of PEG400 or PEG600 is better, and it is also beneficial for the subsequent dissolution of potassium iodide.

[0031] In some embodiments, the temperature of the water used to dissolve the additive is 20–40°C. This temperature condition is more conducive to the dissolution of the prescribed amount of PEG400 or PEG600.

[0032] In some embodiments, the pH value of solution 2 is 2.4 to 2.5.

[0033] In some embodiments, microporous filter membranes with pore sizes of 0.40~0.50μm and 0.20~0.25μm are used for filtration.

[0034] In some embodiments, the mixture is filtered, filled, and then sterilized. Specifically, the sterilization temperature is 120~125℃, and the sterilization time is 10~20min.

[0035] To enable those skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments.

[0036] Example 1 A multi-trace element injection (Ⅲ) has the following formula as shown in Table 1.

[0037] Table 1. Prescription for Example 1

[0038] Its preparation method is as follows: While stirring, add the prescribed amount of xylitol to 60 ml of water for injection at 30°C and stir until completely dissolved. While stirring, add the pre-dissolved prescribed amounts of chromium chloride (CrCl3·6H2O), copper chloride (CuCl2·2H2O), ferric chloride (FeCl3·6H2O), manganese chloride (MnCl2·4H2O), sodium molybdate (Na2MoO4·2H2O), sodium selenite (Na2SeO3), zinc chloride (ZnCl2), potassium iodide (KI), and sodium fluoride (NaF) sequentially, stirring until completely dissolved. Adjust the pH to 2.5 with 1M hydrochloric acid solution and add water for injection to the set total weight. Filter the prepared solution through a 0.45μm ± 0.22μm PES microporous membrane to obtain the filtrate; fill the filtrate into polypropylene ampoules according to the specified volume (10 ml / vial). Sterilize by moist heat at 121°C for 15 min.

[0039] Example 2 A multi-trace element injection (Ⅲ) has the following formula as shown in Table 2.

[0040] Table 2. Prescription for Example 2

[0041] Its preparation method is as follows: While stirring, add the prescribed amounts of xylitol and propylene glycol sequentially to 60 ml of water for injection at 30°C, stirring until completely dissolved. While stirring, add the pre-dissolved prescribed amounts of chromium chloride (CrCl3·6H2O), copper chloride (CuCl2·2H2O), ferric chloride (FeCl3·6H2O), manganese chloride (MnCl2·4H2O), sodium molybdate (Na2MoO4·2H2O), sodium selenite (Na2SeO3), zinc chloride (ZnCl2), potassium iodide (KI), and sodium fluoride (NaF), stirring until completely dissolved. Adjust the pH to 2.5 with 1M hydrochloric acid solution, and add water for injection to the set total weight. Filter the prepared solution through a 0.45μm ± 0.22μm PES microporous membrane to obtain the filtrate; fill the filtrate into polypropylene ampoules according to the specified volume (10 ml / vial). Sterilize by moist heat at 121°C for 15 min.

[0042] Example 3 A multi-trace element injection (Ⅲ) has the following formula as shown in Table 3.

[0043] Table 3. Prescription for Example 3

[0044] Its preparation method is as follows: While stirring, add the prescribed amounts of xylitol and PEG300 sequentially to 60 ml of water for injection at 30°C, and stir until completely dissolved. While stirring, add the pre-dissolved prescribed amounts of chromium chloride (CrCl3·6H2O), copper chloride (CuCl2·2H2O), ferric chloride (FeCl3·6H2O), manganese chloride (MnCl2·4H2O), sodium molybdate (Na2MoO4·2H2O), sodium selenite (Na2SeO3), zinc chloride (ZnCl2), potassium iodide (KI), and sodium fluoride (NaF), and stir until completely dissolved. Adjust the pH to 2.5 with 1M hydrochloric acid solution, and add water for injection to the set total weight. Filter the prepared solution through a 0.45μm ± 0.22μm PES microporous membrane to obtain the filtrate; fill the filtrate into polypropylene ampoules according to the specified volume (10 ml / vial). Sterilize by moist heat at 121°C for 15 min.

[0045] Example 4 A multi-trace element injection (Ⅲ) has the following formula as shown in Table 4.

[0046] Table 4. Prescription for Example 4

[0047] Its preparation method is as follows: While stirring, add the prescribed amounts of xylitol and PEG400 (2.8 g / ml) sequentially to 60 ml of water for injection at 30°C, and stir until completely dissolved. While stirring, add the pre-dissolved prescribed amounts of chromium chloride (CrCl3·6H2O), copper chloride (CuCl2·2H2O), ferric chloride (FeCl3·6H2O), manganese chloride (MnCl2·4H2O), sodium molybdate (Na2MoO4·2H2O), sodium selenite (Na2SeO3), zinc chloride (ZnCl2), potassium iodide (KI), and sodium fluoride (NaF), and stir until completely dissolved. Adjust the pH to 2.5 with 1M hydrochloric acid solution, and add water for injection to the set total weight. Filter the prepared solution through a 0.45 μm ± 0.22 μm PES microporous membrane to obtain the filtrate; fill the filtrate into polypropylene ampoules according to the specified volume (10 ml / vial). Sterilize by moist heat at 121°C for 15 min.

[0048] Example 5 A multi-trace element injection (Ⅲ) has the following formula as shown in Table 5.

[0049] Table 5. Prescription for Example 5

[0050] Its preparation method is as follows: While stirring, add the prescribed amounts of xylitol and PE600 sequentially to 60 ml of water for injection at 30°C, and stir until completely dissolved. While stirring, add the pre-dissolved prescribed amounts of chromium chloride (CrCl3·6H2O), copper chloride (CuCl2·2H2O), ferric chloride (FeCl3·6H2O), manganese chloride (MnCl2·4H2O), sodium molybdate (Na2MoO4·2H2O), sodium selenite (Na2SeO3), zinc chloride (ZnCl2), potassium iodide (KI), and sodium fluoride (NaF), and stir until completely dissolved. Adjust the pH to 2.5 with 1M hydrochloric acid solution, and add water for injection to the set total weight. Filter the prepared solution through a 0.45μm ± 0.22μm PES microporous membrane to obtain the filtrate; fill the filtrate into polypropylene ampoules according to the specified volume (10 ml / vial). Sterilize by moist heat at 121°C for 15 min.

[0051] Example 6 A multi-trace element injection (Ⅲ) has the following formula as shown in Table 6.

[0052] Table 6. Prescription for Example 6

[0053] Its preparation method is as follows: While stirring, add the prescribed amounts of xylitol and PEG400 (0.7 g / ml) sequentially to 60 ml of water for injection at 3°C, and stir until completely dissolved. While stirring, add the pre-dissolved prescribed amounts of chromium chloride (CrCl3·6H2O), copper chloride (CuCl2·2H2O), ferric chloride (FeCl3·6H2O), manganese chloride (MnCl2·4H2O), sodium molybdate (Na2MoO4·2H2O), sodium selenite (Na2SeO3), zinc chloride (ZnCl2), potassium iodide (KI), and sodium fluoride (NaF), and stir until completely dissolved. Adjust the pH to 2.5 with 1M hydrochloric acid solution, and add water for injection to the set total weight. Filter the prepared solution through a 0.45 μm ± 0.22 μm PES microporous membrane to obtain the filtrate; fill the filtrate into polypropylene ampoules according to the specified volume (10 ml / vial). Sterilize by moist heat at 121°C for 15 min.

[0054] Example 7 A multi-trace element injection (Ⅲ) has the following formula as shown in Table 7.

[0055] Table 7. Prescription for Example 7

[0056] Its preparation method is as follows: While stirring, add the prescribed amounts of xylitol and PEG400 (1.4 g / ml) sequentially to 60 ml of water for injection at 30°C, and stir until completely dissolved. While stirring, add the pre-dissolved prescribed amounts of chromium chloride (CrCl3·6H2O), copper chloride (CuCl2·2H2O), ferric chloride (FeCl3·6H2O), manganese chloride (MnCl2·4H2O), sodium molybdate (Na2MoO4·2H2O), sodium selenite (Na2SeO3), zinc chloride (ZnCl2), potassium iodide (KI), and sodium fluoride (NaF), and stir until completely dissolved. Adjust the pH to 2.5 with 1M hydrochloric acid solution, and add water for injection to the set total weight. Filter the prepared solution through a 0.45 μm ± 0.22 μm PES microporous membrane to obtain the filtrate; fill the filtrate into polypropylene ampoules according to the specified volume (10 ml / vial). Sterilize by moist heat at 121°C for 15 min.

[0057] Example 8 A multi-trace element injection (Ⅲ) has the following formula as shown in Table 8.

[0058] Table 8. Prescription for Example 8

[0059] Its preparation method is as follows: While stirring, add the prescribed amounts of xylitol and PEG400 (2.1 g / ml) sequentially to 60 ml of water for injection at 30°C, and stir until completely dissolved. While stirring, add the pre-dissolved prescribed amounts of chromium chloride (CrCl3·6H2O), copper chloride (CuCl2·2H2O), ferric chloride (FeCl3·6H2O), manganese chloride (MnCl2·4H2O), sodium molybdate (Na2MoO4·2H2O), sodium selenite (Na2SeO3), zinc chloride (ZnCl2), potassium iodide (KI), and sodium fluoride (NaF), and stir until completely dissolved. Adjust the pH to 2.5 with 1M hydrochloric acid solution, and add water for injection to the set total weight. Filter the prepared solution through a 0.45 μm ± 0.22 μm PES microporous membrane to obtain the filtrate; fill the filtrate into polypropylene ampoules according to the specified volume (10 ml / vial). Sterilize by moist heat at 121°C for 15 min.

[0060] Example 9 A multi-trace element injection (Ⅲ) has the following formula as shown in Table 9.

[0061] Table 9. Prescription for Example 9

[0062] Its preparation method is as follows: While stirring, add the prescribed amount of xylitol sequentially to 60 ml of water for injection at 30°C, stirring until completely dissolved. While stirring, add the pre-dissolved prescribed amounts of chromium chloride (CrCl3·6H2O), copper chloride (CuCl2·2H2O), ferric chloride (FeCl3·6H2O), manganese chloride (MnCl2·4H2O), sodium molybdate (Na2MoO4·2H2O), sodium selenite (Na2SeO3), zinc chloride (ZnCl2), sodium fluoride (NaF), PEG400 (1.4 g / ml), and potassium iodide (KI), stirring until completely dissolved. Adjust the pH to 2.5 with 1M hydrochloric acid solution, and add water for injection to the set total weight. Filter the prepared solution through a 0.45 μm ± 0.22 μm PES microporous membrane to obtain the filtrate; fill the filtrate into polypropylene ampoules according to the specified volume (10 ml / vial). Sterilize by moist heat at 121°C for 15 min.

[0063] Example 10 A multi-trace element injection (Ⅲ) has the following formula as shown in Table 10.

[0064] Table 10 Prescription for Example 10

[0065] Its preparation method is as follows: Solution 1: While stirring, add the prescribed amount of xylitol to 50 ml of 30°C water for injection and stir until completely dissolved. After the xylitol has completely dissolved, while stirring, add the pre-dissolved prescribed amounts of chromium chloride (CrCl3·6H2O), copper chloride (CuCl2·2H2O), ferric chloride (FeCl3·6H2O), manganese chloride (MnCl2·4H2O), sodium molybdate (Na2MoO4·2H2O), sodium selenite (Na2SeO3), zinc chloride (ZnCl2), and sodium fluoride (NaF), and stir until homogeneous.

[0066] Solution 2: Add the prescribed amount of PEG400 (1.4 mg / ml) to 20 ml of 30°C water for injection while stirring, and stir until completely dissolved. Add the prescribed amount of KI while stirring, and stir until completely dissolved.

[0067] Add solution 2 to solution 1 and stir until well mixed. Adjust the pH to 2.5 with 1 mol / L hydrochloric acid. Add water for injection to the set total weight. Filter the prepared solution through a 0.45 μm ± 0.22 μm PES microporous membrane to obtain the filtrate. Fill the filtrate into polypropylene ampoules according to the specified volume (10 ml / vial). Sterilize by moist heat at 121℃ for 15 min.

[0068] Example 11 A multi-trace element injection (Ⅲ) has the following formula as shown in Table 11.

[0069] Table 11 Prescription for Example 11

[0070] Its preparation method is as follows: Solution 1: While stirring, add the prescribed amount of xylitol to 50 ml of 30°C water for injection and stir until completely dissolved. After the xylitol has dissolved, while stirring, add the pre-dissolved prescribed amounts of chromium chloride (CrCl3·6H2O), copper chloride (CuCl2·2H2O), ferric chloride (FeCl3·6H2O), manganese chloride (MnCl2·4H2O), sodium molybdate (Na2MoO4·2H2O), sodium selenite (Na2SeO3), zinc chloride (ZnCl2), and sodium fluoride (NaF), and stir until homogeneous. Adjust the pH to 2.5 with 1 mol / L hydrochloric acid.

[0071] Solution 2: Add the prescribed amount of PEG400 (1.4 mg / ml) to 20 ml of 30°C water for injection while stirring, and stir until completely dissolved. Adjust the pH to 2.5 with 1 mol / L hydrochloric acid. Add the prescribed amount of KI while stirring, and stir until completely dissolved.

[0072] Add solution 2 to solution 1 and stir well. Add water for injection to the set total weight. Filter the prepared solution through a 0.45μm + 0.22μm PES microporous membrane to obtain the filtrate. Fill the filtrate into polypropylene ampoules according to the specified volume (10ml / vial). Sterilize by moist heat at 121℃ for 15 minutes.

[0073] Example 12 A multi-trace element injection (Ⅲ) has the following formula as shown in Table 12.

[0074] Table 12 Prescription for Example 12

[0075] Its preparation method is as follows: Solution 1: While stirring, add the prescribed amount of xylitol to 50 ml of 20°C water for injection and stir until completely dissolved. After the xylitol has dissolved, while stirring, add the pre-dissolved prescribed amounts of chromium chloride (CrCl3·6H2O), copper chloride (CuCl2·2H2O), ferric chloride (FeCl3·6H2O), manganese chloride (MnCl2·4H2O), sodium molybdate (Na2MoO4·2H2O), sodium selenite (Na2SeO3), zinc chloride (ZnCl2), and sodium fluoride (NaF), and stir until homogeneous. Adjust the pH to 2.5 with 1 mol / L hydrochloric acid.

[0076] Solution 2: Add the prescribed amount of PEG400 (1.4 mg / ml) to 20 ml of 20°C water for injection while stirring, and stir until completely dissolved. Adjust the pH to 2.5 with 1 mol / L hydrochloric acid. Add the prescribed amount of KI while stirring, and stir until completely dissolved.

[0077] Add solution 2 to solution 1 and stir well. Add water for injection to the set total weight. Filter the prepared solution through a 0.45μm + 0.22μm PES microporous membrane to obtain the filtrate. Fill the filtrate into polypropylene ampoules according to the specified volume (10ml / vial). Sterilize by moist heat at 121℃ for 15 minutes.

[0078] Example 13 A multi-trace element injection (Ⅲ) has the following formula as shown in Table 13.

[0079] Table 13 Prescription for Example 13

[0080] Its preparation method is as follows: Solution 1: While stirring, add the prescribed amount of xylitol to 50 ml of 40°C water for injection and stir until completely dissolved. After the xylitol has dissolved, while stirring, add the pre-dissolved prescribed amounts of chromium chloride (CrCl3·6H2O), copper chloride (CuCl2·2H2O), ferric chloride (FeCl3·6H2O), manganese chloride (MnCl2·4H2O), sodium molybdate (Na2MoO4·2H2O), sodium selenite (Na2SeO3), zinc chloride (ZnCl2), and sodium fluoride (NaF), and stir until homogeneous. Adjust the pH to 2.5 with 1 mol / L hydrochloric acid.

[0081] Solution 2: Add the prescribed amount of PEG400 (1.4 mg / ml) to 20 ml of 40°C water for injection while stirring, and stir until completely dissolved. Adjust the pH to 2.5 with 1 mol / L hydrochloric acid. Add the prescribed amount of KI while stirring, and stir until completely dissolved.

[0082] Add solution 2 to solution 1 and stir well. Add water for injection to the set total weight. Filter the prepared solution through a 0.45μm + 0.22μm PES microporous membrane to obtain the filtrate. Fill the filtrate into polypropylene ampoules according to the specified volume (10ml / vial). Sterilize by moist heat at 121℃ for 15 minutes.

[0083] The results of the iodine loss investigation before and after sterilization in each embodiment are shown in Table 14.

[0084] Table 14 Results of Iodine Loss Before and After Sterilization in Examples 1-11

[0085] Table 14 shows that the iodine loss rate after sterilization of the sample prepared according to Example 1 (original formulation) was 20.4%; the iodine loss rate after sterilization of the samples prepared according to Examples 2-5, especially Examples 4 and 5, was significantly improved compared to the original formulation, with Example 4 showing an iodine loss rate of only 6.8%; the iodine loss rate after sterilization of the samples prepared according to Examples 4, 6-8 was affected by the amount of PEG400 in the formulation, and the iodine loss rate after sterilization of the sample prepared in Example 7 was relatively low at 5.8%. Figure 1 As shown.

[0086] The sample prepared according to the different preparation methods in Examples 7, 9-11 had a relatively low iodine loss rate after sterilization, with Example 11 having an iodine loss rate of 1.5%. This indicates that the sample prepared by the method in Example 11 further reduced the iodine loss rate after sterilization. The iodine loss rate of the 0-day samples prepared according to Examples 11-13 did not exceed 2% after sterilization.

[0087] In summary, the experimental data in Table 14 demonstrate that the iodine loss rate of the various trace element injections (III) obtained using the formulations and preparation methods studied in Examples 11-13 is significantly improved compared to the original formulation (Example 1), and does not exceed 2%.

[0088] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A multi-trace element injection solution, characterized in that, It includes an active ingredient, a stabilizer, and water. The active ingredient includes chromium chloride, copper chloride, ferric chloride, manganese chloride, sodium molybdate, sodium selenite, zinc chloride, potassium iodide, and sodium fluoride. The stabilizer includes xylitol, a pH adjuster, and additives. The additives are PEG400 or PEG600.

2. The multi-trace element injection solution as described in claim 1, characterized in that, The mass of the additive per milliliter of water is 0.5~3.0g, 0.7~2.8g, or 1.3~1.5g.

3. The multi-trace element injection solution as described in claim 1, characterized in that, The pH of the multi-trace element injection solution is 2.4~2.

5.

4. The multi-trace element injection solution as described in claim 1, characterized in that, The mass of xylitol in each milliliter of water is 0.25~0.35g.

5. The multi-trace element injection solution as described in claim 1, characterized in that, The molar concentrations of the active ingredients per milliliter of water are as follows: chromium chloride 0.015~0.025 μmol, copper chloride 0.50~0.70 μmol, ferric chloride 1.5~2.5 μmol, manganese chloride 0.05~0.15 μmol, sodium molybdate 0.015~0.025 μmol, sodium selenite 0.05~0.15 μmol, zinc chloride 7.0~8.5 μmol, potassium iodide 0.015~0.025 μmol, and sodium fluoride 4.5~5.5 μmol; Alternatively, the molar concentrations of the active ingredients per milliliter of water are as follows: chromium chloride 0.018~0.022 μmol, copper chloride 0.55~0.65 μmol, ferric chloride 1.8~2.2 μmol, manganese chloride 0.08~0.12 μmol, sodium molybdate 0.018~0.022 μmol, sodium selenite 0.08~0.12 μmol, zinc chloride 7.5~8.0 μmol, potassium iodide 0.018~0.022 μmol, and sodium fluoride 4.8~5.2 μmol; Alternatively, the molar concentrations of the active ingredients per milliliter of water are as follows: chromium chloride 0.019~0.021 μmol, copper chloride 0.59~0.61 μmol, ferric chloride 1.9~2.1 μmol, manganese chloride 0.09~0.11 μmol, sodium molybdate 0.019~0.021 μmol, sodium selenite 0.09~0.11 μmol, zinc chloride 7.6~7.8 μmol, potassium iodide 0.019~0.021 μmol, and sodium fluoride 4.9~5.1 μmol.

6. A method for preparing a multi-trace element injection solution, characterized in that, The raw material composition of the multi-trace element injection solution is the same as that of the multi-trace element injection solution according to any one of claims 1 to 5, and includes the following steps: Dissolve xylitol in water, then add chromium chloride, copper chloride, ferric chloride, manganese chloride, sodium molybdate, sodium selenite, zinc chloride, and sodium fluoride and mix well. Then adjust the pH of the solution to the set value using a pH adjuster to obtain solution 1. Dissolve the additive in water, then adjust the pH of the solution to the set value using a pH adjuster, and then add potassium iodide to dissolve completely to obtain solution 2; Mix solution 1 and solution 2, add water, and filter to obtain the final product.

7. The preparation method according to claim 6, characterized in that, Xylitol is dissolved in 45-55% water according to the prescription. Alternatively, the water temperature for dissolving xylitol is 20~40℃; Alternatively, the pH value of solution 1 is 2.4~2.

5.

8. The preparation method according to claim 6, characterized in that, Use 15-25% water-soluble additives as prescribed; Alternatively, the water temperature for dissolving the additive should be 20~40℃; Alternatively, the pH value of solution 2 is 2.4~2.

5.

9. The preparation method according to claim 6, characterized in that, Filtration was performed using microporous membranes with pore sizes of 0.40~0.50μm and 0.20~0.25μm.

10. The preparation method according to claim 6, characterized in that, After filtration, the mixture is filled and then sterilized.

Images