A vitamin K1 injection solution and its preparation method

Abstract

The application belongs to the technical field of pharmaceutical preparation, and particularly relates to a vitamin K1 injection and a preparation method thereof. The vitamin K1 injection provided by the application is prepared from an active ingredient vitamin K1, excipients and water for injection; wherein the excipients include a solubilizer, bile acid and phospholipid, a cosolvent, an alkaline reagent, and a pH regulator; wherein the mass ratio of the bile acid to the phospholipid is 0.5-0.8:1. The vitamin K1 injection does not contain a surfactant, and does not need to use an organic solvent in the preparation process. On the premise of not increasing high equipment cost investment, the product with the required quality is obtained, the clarity, color, particle size distribution, pH value, main ingredient content, related substance content and stability of the product are consistent with those of the original preparation, the safety of clinical use is significantly improved, and the product has a great commercial application prospect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a vitamin K1 injection and its preparation method. Background Technology

[0002] The causes of gastrointestinal bleeding in newborns are complex, but its essence is stress ulceration. Under the influence of stressful events such as shock, infection, traumatic brain injury, and asphyxia, the compensatory mechanisms of the neuroendocrine system are activated, sympathetic nerve excitability is enhanced, catecholamine release increases, promoting massive gastric acid secretion and stimulating the gastrointestinal tract to induce bleeding. Currently, the mechanism of coagulation dysfunction caused by gastrointestinal bleeding is not fully understood, but it is generally believed to be caused by inflammatory reactions, tissue damage, insufficient blood perfusion, and acidosis, leading to endothelial cell damage, activation of protein C, and inhibition of thrombin secretion. Following neonatal gastrointestinal bleeding, insufficient tissue perfusion leads to the loss of coagulation factors and decreased blood volume, and the production of large amounts of lactic acid causes acidosis, exacerbating coagulation dysfunction.

[0003] Vitamin K1 deficiency bleeding is a common type of gastrointestinal bleeding in newborns. Due to poor placental permeability, vitamin K1 is stored in low levels in the blood and liver of newborns. However, it plays a significant role in the synthesis of clotting factors in the liver. A deficiency prevents clotting factors from carboxylating and binding to calcium to produce clotting activity, thus preventing them from participating in the clotting process and resulting in inability to clot. Therefore, vitamin K1 supplementation can effectively increase the concentration and activity of vitamin K1-dependent clotting factors in plasma, thereby promoting coagulation.

[0004] However, vitamin K1 is a fat-soluble vitamin and is insoluble in water. To make it suitable for newborns, vitamin K1 injections are used clinically. However, currently available vitamin K1 injections in China have serious adverse reactions. Researchers generally believe these adverse reactions may be related to the cosolvents Tween-80 and propylene glycol contained in the injection. Therefore, some studies have avoided using these cosolvents. For example, patent CN 105997869 A discloses a method for preparing mixed micelles of vitamin K1, in which vitamin K1, phospholipids, and bile salts are dissolved in an organic solvent, and then the organic solvent is removed by lyophilization to obtain a mixed micelle-encapsulated active ingredient powder. After redissolving, the powder is filled and sterilized to obtain a vitamin K1 injection formulation. This preparation process introduces an organic solvent, which is subsequently removed by lyophilization. Patent CN115554241 A discloses a method for preparing mixed micelles of vitamin K1. Phospholipids and bile salts are dissolved in water for injection, stirred until a semi-solid viscous state is formed, dried at 60°C until the moisture content is ≤3%, and then granulated by a swing granulation process to obtain a mixed micelle composition. Cosolvents 15-hydroxystearic acid polyethylene glycol ester and poloxamer 188 are added, and the active pharmaceutical ingredient is then added, stirred to dissolve, and filled and sterilized to obtain a vitamin K1 injection formulation. This preparation process requires drying at 60°C, uses swing granulation technology, and introduces multiple cosolvents. Patent CN 110876719 A discloses a method for preparing mixed micelles of vitamin K1. Vitamin K1, phospholipids, and bile salts are dissolved in ethanol, and then an inert gas is passed through the solution to evaporate and remove the ethanol, resulting in a semi-solid mixture. This mixture is then dissolved again in water, filled, and sterilized to obtain a vitamin K1 injection formulation. This preparation process uses the organic solvent ethanol. In April 2016, Wang Yanan et al. published an article titled "Preparation and In Vitro Evaluation of Vitamin K1 Phospholipid / Bile Salt Mixed Micelles" in the journal *Science, Technology and Engineering*. They prepared vitamin K1, phospholipid / bile salt mixed micelles using a thin-film dispersion-ultrasound method. The drugs and phospholipids / bile salts were dissolved in chloroform, and after vacuum distillation to form a film, water was added to dissolve and form the mixed micelles. He Dianhong et al., from the School of Traditional Chinese Medicine at Beijing University of Chinese Medicine, published an article titled "Application of Bile Salt / Phospholipid Mixed Micellar Systems in Pharmaceutics," which also used a thin-film dispersion method to prepare mixed micelles. However, products prepared using the thin-film dispersion method have disadvantages in commercial production, including difficulty in achieving mass production, the presence of organic solvents, and reduced safety for clinical use, which are detrimental to the safe production of pharmaceuticals.

[0005] In summary, current methods for preparing vitamin K1 injections all suffer from problems such as the use of organic solvents, the addition of large amounts of surfactants, or cumbersome processes, posing safety risks to neonatal use and hindering industrial production. Summary of the Invention

[0006] Therefore, the present invention provides a vitamin K1 injection solution and a method for preparing the same. This vitamin K1 injection solution requires no additional surfactants, has a simple preparation process, does not require organic solvents, and offers higher safety and production feasibility.

[0007] To solve the above technical problems, the first aspect of the present invention provides a vitamin K1 injection solution, which is prepared from the active ingredient vitamin K1, excipients and water for injection; the excipients include: solubilizers—bile acids and phospholipids, cosolvents—alkaline reagents, and pH adjusters; wherein the mass ratio of bile acids to phospholipids is 0.5 to 0.8:1.

[0008] The inventors accidentally discovered during their research that when bile salts were replaced with bile acids and used in combination with phospholipids and alkaline reagents, the solubility of vitamin K1 in water was significantly improved, and vitamin K1 injection solution with the required clarity and color could be obtained quickly without the need for additional surfactants or organic solvents.

[0009] Preferably, the amount of vitamin K1 is 10.0 g / L, the amount of bile acid is 44.3–54.6 g / L, the amount of phospholipid is 75.6–78.8 g / L, and the amount of alkaline reagent is 4.45–6.25 g / L.

[0010] Preferably, the bile acid is selected from glycocholic acid, deoxycholic acid, or cholic acid.

[0011] Preferably, the phospholipid used is selected from soybean phospholipids, lecithin, egg yolk lecithin, or distearate phosphatidylcholine.

[0012] Preferably, the alkaline reagent is selected from sodium hydroxide, potassium hydroxide, magnesium hydroxide, or sodium carbonate.

[0013] In this invention, the excipients bile acids, phospholipids and alkaline reagents work together to promote the dissolution of vitamin K1 in water, simplifying the formulation and improving the safety of clinical medication.

[0014] Preferably, the pH of the injection solution is 5.5 to 6.5, more preferably 6.0 to 6.5, and even more preferably 6.1 to 6.4.

[0015] A second aspect of the present invention provides a method for preparing the above-mentioned vitamin K1 injection solution, comprising the steps of: adding water for injection to a solution preparation container, sequentially adding bile acids, phospholipids and vitamin K1, stirring evenly, adding the alkaline reagent, stirring until the solution is clear, adjusting the pH, making up to the full volume with water for injection, filtering, filling and sterilizing to obtain the vitamin K1 injection solution preparation.

[0016] The method for preparing vitamin K1 injection provided by this invention does not require the addition of organic solvents to aid dissolution during the preparation process, nor does it require the use of complex processes or expensive equipment. The clarity, color, particle size distribution, pH value, main component content, related substance content, and stability of the obtained vitamin K1 injection are comparable to those of the original formulation.

[0017] Preferably, the temperature of the water for injection during the preparation process is 45–80°C, for example, 50°C, 60°C, 70°C or 75°C.

[0018] Preferably, the stirring is carried out by stirring with a stirring paddle, high-shear stirring, or high-pressure homogenization.

[0019] Preferably, the sterilization conditions are: sterilization at 121°C for 8–15 minutes.

[0020] The beneficial effects of this invention are as follows: The vitamin K1 injection solution provided by this invention does not contain surfactants and does not require the use of organic solvents in the preparation process. Without increasing the investment in high equipment costs, a product that meets the quality requirements is obtained. Its clarity, color, particle size distribution, pH value, main component content, related substance content and stability are consistent with the original formulation, which significantly improves the safety of clinical use and has great commercial application prospects. Detailed Implementation

[0021] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments. It should be understood that the specific embodiments described herein are for illustrative purposes only and are not intended to limit the invention.

[0022] The injection solutions prepared in the following examples and comparative examples are all 1 mL / vial, and each vial contains 10 mg of vitamin K1.

[0023] Example 1

[0024] This embodiment provides a vitamin K1 injection solution, the formulation of which is shown in Table 1, and the preparation steps include:

[0025] (1) Preparation of the medicine solution:

[0026] Add approximately 60% of the total volume of water for injection to the mixing tank, then add the prescribed amounts of glycocholic acid, soybean lecithin, and vitamin K1 sequentially. Heat to 70°C and maintain this temperature while stirring until homogeneous. Add the prescribed amount of sodium hydroxide solution to the mixing tank, heat to 80°C, and maintain this temperature while stirring until the solution becomes a pale yellow, clear liquid. Adjust the pH to 5.0–6.5 with hydrochloric acid solution, then weigh to the final volume with water for injection and stir until homogeneous. Filter the solution sequentially through a 0.2 μm polyethersulfone pleated filter cartridge into the filling tank.

[0027] (2) Filling, nitrogen filling and sealing are carried out in sequence, and then sterilized at 121℃ for 15 minutes. Leak detection, light inspection and packaging are performed to obtain vitamin K1 injection preparation.

[0028] Example 2

[0029] This embodiment provides a vitamin K1 injection solution, the formulation of which is shown in Table 1, and the preparation steps include:

[0030] (1) Preparation of the medicine solution:

[0031] Add approximately 60% of the total volume of water for injection to the mixing tank, then add the prescribed amounts of deoxycholic acid, egg yolk lecithin, and vitamin K1 sequentially. Heat to 50°C and maintain this temperature while stirring until homogeneous. Add the prescribed amount of sodium hydroxide solution to the mixing tank, heat to 80°C, and maintain this temperature while stirring until the solution becomes a pale yellow, clear liquid. Adjust the pH to 5.0–6.5 with hydrochloric acid solution, then weigh to the final volume with water for injection and stir until homogeneous. Filter the solution sequentially through a 0.2 μm polyethersulfone pleated filter cartridge into the filling tank.

[0032] (2) Filling, nitrogen filling and sealing are carried out in sequence, and then sterilized at 121℃ for 12 minutes. Leak detection, light inspection and packaging are performed to obtain vitamin K1 injection preparation.

[0033] Example 3

[0034] This embodiment provides a vitamin K1 injection solution, the formulation of which is shown in Table 1, and the preparation steps include:

[0035] (1) Preparation of the medicine solution:

[0036] Add approximately 60% of the total volume of water for injection to the mixing tank, then add the prescribed amounts of cholic acid, soybean lecithin, and vitamin K1 sequentially. Heat to 60°C and maintain this temperature while stirring until homogeneous. Add the prescribed amount of sodium hydroxide solution to the mixing tank, heat to 75°C, and maintain this temperature while stirring until the solution becomes a pale yellow, clear liquid. Adjust the pH to 5.0–6.5 with hydrochloric acid solution, then weigh to the final volume with water for injection and stir until homogeneous. Filter the solution sequentially through a 0.2 μm polyethersulfone pleated filter cartridge into the filling tank.

[0037] (2) Filling, nitrogen filling and sealing are carried out in sequence, and then sterilized at 121℃ for 10 minutes. Leak detection, light inspection and packaging are performed to obtain vitamin K1 injection preparation.

[0038] Example 4

[0039] This embodiment provides a vitamin K1 injection solution, the formulation of which is shown in Table 1, and the preparation steps include:

[0040] (1) Preparation of the medicine solution:

[0041] Add approximately 60% of the total volume of water for injection to the mixing tank, then add the prescribed amounts of glycocholic acid, soybean lecithin, and vitamin K1 sequentially. Heat to 70°C and maintain this temperature while stirring until homogeneous. Add the prescribed amount of potassium hydroxide solution to the mixing tank, heat to 80°C, and maintain this temperature while stirring until the solution becomes a pale yellow, clear liquid. Adjust the pH to 5.0–6.5 with hydrochloric acid solution, then weigh to the final volume with water for injection and stir until homogeneous. Filter the solution sequentially through a 0.2 μm polyethersulfone pleated filter cartridge into the filling tank.

[0042] (2) Filling, nitrogen filling and sealing are carried out in sequence, and then sterilized at 121℃ for 8 minutes. Leak detection, light inspection and packaging are performed to obtain vitamin K1 injection preparation.

[0043] Example 5

[0044] This embodiment provides a vitamin K1 injection solution, the formulation of which is shown in Table 1, and the preparation steps include:

[0045] (1) Preparation of the medicine solution:

[0046] Add approximately 60% of the total volume of water for injection to the mixing tank, then add the prescribed amounts of glycocholic acid, distearate phosphatidylcholine, and vitamin K1 sequentially. Heat to 70°C and maintain this temperature while stirring under high shear until homogeneous. Add the prescribed amount of sodium hydroxide solution to the mixing tank, heat to 80°C, and maintain this temperature while stirring under high shear until the solution becomes a pale yellow, clear liquid. Adjust the pH to 5.0–6.5 with hydrochloric acid solution, then weigh to the final volume with water for injection and stir until homogeneous. Filter the solution sequentially through a 0.2 μm polyethersulfone pleated filter cartridge into the filling tank.

[0047] (2) Filling, nitrogen filling and sealing are carried out in sequence, and then sterilized at 121℃ for 15 minutes. Leak detection, light inspection and packaging are performed to obtain vitamin K1 injection preparation.

[0048] Example 6

[0049] This embodiment provides a vitamin K1 injection solution, the formulation of which is shown in Table 1, and the preparation steps include:

[0050] (1) Preparation of the medicine solution:

[0051] Add approximately 60% of the total volume of water for injection to the mixing tank, then add the prescribed amounts of glycocholic acid, soybean lecithin, and vitamin K1 sequentially. Heat to 45°C and maintain this temperature while stirring under high shear until homogeneous. Add the prescribed amount of sodium hydroxide solution to the mixing tank, heat to 80°C, maintain the temperature, and homogenize under high pressure until the solution becomes a pale yellow, clear liquid. Adjust the pH to 5.0–6.5 with hydrochloric acid solution, then weigh to the final volume with water for injection and stir until homogeneous. Filter the solution sequentially through a 0.2 μm polyethersulfone pleated filter cartridge into the filling tank.

[0052] (2) Filling, nitrogen filling and sealing are carried out in sequence, and then sterilized at 121℃ for 12 minutes. Leak detection, light inspection and packaging are performed to obtain vitamin K1 injection preparation.

[0053] Comparative Example 1

[0054] This comparative example provides a vitamin K1 injection solution, the formulation of which is shown in Table 1. The preparation steps include:

[0055] (1) Preparation of the medicine solution:

[0056] Add approximately 60% of the total volume of water for injection to the mixing tank, then add the prescribed amounts of Tween 80, soybean lecithin, and vitamin K1 sequentially. Heat to 45°C and maintain this temperature while stirring under high shear until homogeneous. Add the prescribed amount of sodium hydroxide solution to the mixing tank, heat to 80°C, maintain the temperature, and homogenize under high pressure until the solution becomes a pale yellow, clear liquid. Adjust the pH to 5.0–6.5 with hydrochloric acid solution, then weigh to the final volume with water for injection and stir until homogeneous. Filter the solution sequentially through a 0.2 μm polyethersulfone pleated filter cartridge into the filling tank.

[0057] (2) Filling, nitrogen filling and sealing are carried out in sequence, and then sterilized at 121℃ for 12 minutes. Leak detection, light inspection and packaging are performed to obtain vitamin K1 injection preparation.

[0058] Comparative Example 2

[0059] This comparative example provides a vitamin K1 injection solution, the formulation of which is shown in Table 1. The preparation steps include:

[0060] (1) Preparation of the medicine solution:

[0061] Add approximately 60% of the total volume of water for injection to the mixing tank, then add the prescribed amounts of glyceryl monolaurate, soybean lecithin, and vitamin K1 sequentially. Heat to 45°C and maintain this temperature while stirring under high shear until homogeneous. Add the prescribed amount of sodium hydroxide solution to the mixing tank, heat to 80°C, maintain the temperature, and homogenize under high pressure until the solution becomes a pale yellow, clear liquid. Adjust the pH to 5.0–6.5 with hydrochloric acid solution, then weigh to the final volume with water for injection and stir until homogeneous. Filter the solution sequentially through a 0.2 μm polyethersulfone pleated filter cartridge into the filling tank.

[0062] (2) Filling, nitrogen filling and sealing are carried out in sequence, and then sterilized at 121℃ for 12 minutes. Leak detection, light inspection and packaging are performed to obtain vitamin K1 injection preparation.

[0063] Table 1

[0064]

[0065] Test Example 1

[0066] The clarity and color of the vitamin K1 injection preparations prepared in Examples 1-6 and Comparative Examples 1-2, as well as the original formulation (batch F4118F01), were tested. The test method was as follows: The test solution and an equal volume of turbidity standard solution were placed in paired glass tubes for turbidity comparison. After the turbidity standard solution was prepared for 5 minutes, the tubes were placed vertically under a shed lamp in a dark room with an illuminance of 1000-2000 lx. The results were observed and compared from a horizontal direction (see General Chapter 0902, Part IV, Chinese Pharmacopoeia 2020). The results are shown in Table 2.

[0067] Table 2

[0068]

[0069] As can be seen from the test data in Table 2, the clarity of the micelle vitamin K1 injection prepared in Examples 1 to 6 of this invention is consistent with that of the original preparation and meets the requirements. However, the clarity of the vitamin K1 injection obtained by using other types of surfactants in Comparative Examples 1 and 2 has decreased and does not meet the requirements.

[0070] Test Example 2

[0071] The particle size of the vitamin K1 injection preparations prepared in Examples 1-6 and Comparative Examples 1-2, as well as the original preparation (batch F4118F01), was measured (instrument: nanoparticle size analyzer, manufacturer: Malvern, model: ZEN3600). The results are shown in Table 3.

[0072] Table 3

[0073]

[0074] As can be seen from the test data in Table 3, the particle size distribution of the micelle vitamin K1 injection prepared in Examples 1 to 6 of this invention is basically consistent and is close to that of the original preparation. However, the particle size of the vitamin K1 injection obtained by using other types of surfactants in Comparative Examples 1 and 2 is significantly larger.

[0075] Test Example 3

[0076] The pH of the vitamin K1 injection preparations obtained in Examples 1-6 and Comparative Examples 1-2, as well as the original formulation (batch F4118F01), was measured (instrument: pH meter, manufacturer: Mettler Toledo, model: Seven Compact S10). The detection method was the same as that in General Chapter 0631 of Part IV of the Chinese Pharmacopoeia 2020. The test results are shown in Table 4.

[0077] Table 4

[0078] pH value Batch F4118F01 (Original Research Kit) 6.1 Example 1 6.2 Example 2 6.4 Example 3 6.3 Example 4 5.8 Example 5 5.9 Example 6 6.1 Comparative Example 1 7.5 Comparative Example 2 6.8

[0079] As can be seen from the test data in Table 4, the pH values ​​of the micelle vitamin K1 injections prepared in Examples 1 to 6 of this invention are basically consistent and are basically the same as the original formulation, while the pH values ​​of the vitamin K1 injections obtained by using other types of surfactants in Comparative Examples 1 to 2 are significantly higher.

[0080] Test Example 4

[0081] The content and related substances of vitamin K1 injection preparations obtained in Examples 1-6 and Comparative Examples 1-2, as well as the original preparation (batch F4118F01), were determined:

[0082] (I) Content Detection

[0083] (1.1) Instrument: High performance liquid chromatograph, manufacturer: Shimadzu, Japan, model: LC-20A.

[0084] (1.2) Chromatographic conditions:

[0085] Column: Octadecylsilane-bonded silica gel as the packing material (Agilent ZORBAX Eclipe XDB-C184.6*150mm 5μm column or equivalent performance column).

[0086] Mobile phase: anhydrous ethanol: water (90v: 10v),

[0087] Detection wavelength: 254nm

[0088] Column temperature: 30℃

[0089] Flow rate 1 mL / min

[0090] Injection volume: 10 μL.

[0091] The measurement results are shown in Table 5.

[0092] (II) Related Substances Testing

[0093] (1.1) Instrument: High performance liquid chromatograph, manufacturer: Shimadzu, Japan, model: LC-20A.

[0094] (1.2) Chromatographic conditions:

[0095] Column: Octadecylsilane-bonded silica gel as the packing material (Agilent ZORBAX Eclipe XDB-C184.6*150mm 5μm column or equivalent performance column).

[0096] Mobile phase: Anhydrous ethanol as mobile phase A, water as mobile phase B, elution procedure as follows:

[0097] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 60 40 15 80 20 45 95 5 55 95 5 55.1 60 40 65 60 40

[0098] Detection wavelength: 270nm

[0099] Column temperature: 30℃

[0100] Flow rate 1 mL / min

[0101] Injection volume: 10 μL.

[0102] The measurement results are shown in Table 5.

[0103] Table 5

[0104] <![CDATA[Vitamin K1 content]]> Content of related substances Batch F4118F01 (Original Research Kit) 102.0％ 4.0％ Example 1 100.6％ 3.5％ Example 2 99.4％ 3.8％ Example 3 99.7％ 4.1％ Example 4 101.1％ 3.7％ Example 5 100.0％ 4.1％ Example 6 100.8％ 3.4％ Comparative Example 1 98.4％ 5.3％ Comparative Example 2 99.1％ 4.9％

[0105] As can be seen from the test data in Table 5, the content of vitamin K1 and related substances in the micelle vitamin K1 injection prepared in Examples 1 to 6 of this invention are basically the same and are basically the same as the original preparation. However, the content of vitamin K1 in the vitamin K1 injection obtained by using other types of surfactants in Comparative Examples 1 to 2 is relatively low, while the content of related substances is relatively high.

[0106] Test Example 5

[0107] Stability tests were conducted on the vitamin K1 injection formulations prepared in Examples 1-6 and Comparative Examples 1-2, as well as the original formulation (batch F4118F01). The methods and results are as follows:

[0108] The vitamin K1 injection preparations obtained in Examples 1-6 and Comparative Examples 1-2 were stored continuously for 6 months in an environment with a temperature of 25℃±2℃ and a humidity of 60%RH±5%RH. After that, the vitamin K1 content and related substance content of each preparation were tested, the properties and clarity of the preparations were observed, and the average particle size and pH value were measured. The results are shown in Table 6.

[0109] Table 6

[0110]

[0111]

[0112] As can be seen from the long-term 6-month experimental results in Table 6, the product quality of the micelle vitamin K1 injection prepared in Examples 1 to 6 of this invention is stable and basically consistent with the original formulation.

[0113] The above description is merely a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A vitamin K1 injection solution, characterized in that, It is formulated with active ingredient vitamin K1, excipients and water for injection; The excipients include: solubilizers—bile acids and phospholipids, cosolvents—alkaline reagents, and pH adjusters; wherein the mass ratio of bile acids to phospholipids is 0.5~0.8:1, and the phospholipids are selected from soybean phospholipids, lecithin, or egg yolk lecithin; The preparation steps of the vitamin K1 injection solution include: adding water for injection into the solution preparation container, adding bile acids, phospholipids and vitamin K1 in sequence, stirring evenly, adding the alkaline reagent, stirring until the solution is clear, adjusting the pH, making up to the full volume with water for injection, filtering, filling and sterilizing to obtain the vitamin K1 injection solution preparation. The dosage of vitamin K1 is 10.0 g / L, the dosage of bile acids is 44.3~54.6 g / L, the dosage of phospholipids is 75.6~78.8 g / L, and the dosage of alkaline reagent is 4.45~6.25 g / L; the bile acids are selected from glycocholic acid, deoxycholic acid, or cholic acid; the alkaline reagent is selected from sodium hydroxide or potassium hydroxide; the pH of the injection solution is 5.5~6.5; and the temperature of the water for injection during preparation is 45~80℃.

2. The vitamin K1 injection solution as described in claim 1, characterized in that, The stirring is carried out by stirring with a stirring paddle, high-shear stirring, or high-pressure homogenization.

3. The vitamin K1 injection solution as described in claim 1, characterized in that, The sterilization conditions are: sterilization at 121℃ for 8~15 minutes.

Images