Vitamin K1 injection and preparation method thereof

Abstract

The invention relates to a vitamin K1 injection and a preparation method thereof, and relates to the technical field of medicines, the vitamin K1 injection comprises vitamin K1, a solubilizer, an amino acid compound, a metal ion chelating agent, an osmotic pressure regulator and the like; the preparation method comprises the following steps: weighing a solvent, adding the solvent into a liquid preparation tank, keeping the temperature, adding the solubilizer, the vitamin K1, the metal ion chelating agent, the osmotic pressure regulator and the amino acid compound according to the prescription amount, and sequentially stirring until the components are dissolved; adjusting the pH value, adding a solvent, and fixing the weight to the total liquid preparation amount to obtain a liquid medicine; and filtering, filling and sterilizing at high temperature to obtain the injection. The solubilizer and the amino acid compound are combined for use, the clouding point of the solubilizer is increased, the clouding phenomenon in the high-temperature sterilization process is eliminated, and visible foreign matter and insoluble particles meet the requirements. The amino acid compound and the metal ion chelating agent are combined for use, the growth speed of related substances is reduced, and the stability of the injection is improved. In addition, by adopting the new solubilizer, the overall safety of the injection is improved.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a vitamin K1 injection and a preparation method thereof. Background Art

[0002] Vitamin K1 (Phytonadione) is a mixture of trans and cis isomers of 2-methyl-3-(3,7,11,15-tetramethyl-2-hexadecene)-1,4-naphthalenedione, with a molecular formula of C 31 H 46 O2, molecular weight is 450.71. Vitamin K1 is a yellow to orange clear viscous liquid, odorless or almost odorless, and easily decomposed by light.

[0003] The 2020 edition of the Chinese Pharmacopoeia includes vitamin K1 injection, with a main drug concentration of 10 mg / ml, a yellow liquid sterile aqueous dispersion. Vitamin K1 injection is used for ischemia caused by vitamin K deficiency, such as bleeding caused by obstructive jaundice, biliary fistula, chronic diarrhea, etc., hypoprothrombinemia caused by coumarins, sodium salicylate, etc., neonatal hemorrhage, and vitamin K deficiency in the body caused by long-term use of broad-spectrum antibiotics. Vitamin K1 injection is one of the commonly used clinical drugs. It has a complex production process and strict storage requirements. It needs to be shading, airtight, and antifreeze. If oil droplets precipitate or stratify during storage, it should not be used; it is easy to deteriorate during storage. According to the quality reports published by various provinces, the relevant substances of vitamin K1 injection produced by multiple manufacturers are unqualified. From the physical and chemical properties of the raw materials, the information included in the 2020 edition of the Chinese Pharmacopoeia, and the quality reports of various provinces, it can be seen that domestic vitamin K1 injection generally has visible foreign matter and related substances that are unqualified during the shelf life. In addition, vitamin K1 injection has been launched in China. The [Adverse Reactions] section in the instructions clearly states that the product may cause symptoms such as low blood pressure, increased heart rate, and hemolysis, leading to allergic and allergic-like reactions.

[0004] Currently, most of the vitamin K1 injections available in China are solubilized with polysorbate 80 (Tween-80). For example, CN101327202B discloses a vitamin K1 powder for injection, which is composed of active ingredient vitamin K1, a solubilizer, a stabilizer, an excipient and water for injection, and is finally obtained by low-temperature freeze-drying; wherein the solubilizer is Tween-80. The tan point of Tween-80 is about 93°C. If the hydrogen bond between the polyoxyethylene chain of Tween-80 and water is broken during high-temperature sterilization, its solubility in water will drop sharply and precipitate, and the solution will become turbid or stratified; CN105287366B discloses a vitamin K1 injection and a preparation method thereof. After nitrogen filling and filling, it is sterilized by rotation at 121°C for 12 minutes or prepared by aseptic method. Rotary sterilization is used to solve the problem of visible foreign matter unqualified due to the tanning phenomenon in the sterilization process; CN101129345B discloses a vitamin K1 injection and a production method thereof. It is sterilized after filling, and sterilization is carried out by 100°C hot pressure steam sterilization for 30 minutes. During sterilization, the method of sterilization is carried out by turning over and sterilizing or by inverted sterilization. Rotary sterilization and inverted sterilization are used to solve the related problems caused by the tanning phenomenon in the sterilization process, and the production process is cumbersome. In addition, from the quality reports published by various provinces, the vitamin K1 injections produced by multiple manufacturers are all unqualified, indicating that the use of special sterilization processes cannot avoid the problem of visible foreign matter in the subsequent stability process. Therefore, the phenomenon of blistering and stratification after sterilization limits the use of terminal sterilization processes and greatly increases the cost of sterilization. In addition, the injection has poor stability and safety, and may cause manifestations such as reduced blood pressure, increased heart rate, and hemolysis after use, leading to allergic and anaphylactic reactions. CN104415336B discloses a composition that can eliminate the blistering phenomenon of poloxamer, and the composition is composed of poorly soluble drugs, poloxamer, polyols and water for injection. It uses polyols to eliminate the blistering phenomenon, and hydroxy compounds may produce aldehyde substances after sterilization, affecting drug safety; in addition, the residual peroxides in PEG substances affect the stability of substances sensitive to oxygen.

[0005] Therefore, it is necessary to develop a vitamin K1 injection that is clear and does not cause clouding after terminal sterilization, and has good injection stability and high safety. Summary of the invention

[0006] The object of the present invention is to provide a vitamin K1 injection and a preparation method thereof. The injection prepared by the method does not cause blistering during the sterilization process, the sample liquid is clear after sterilization, the levels of visible foreign matter and insoluble particles are in compliance, the stability is good, and the safety is high; the problems of blistering and stratification, poor stability, and poor safety of the existing vitamin K1 injection after sterilization are solved.

[0007] The technical solution provided by the present invention is as follows:

[0008] A first aspect of the present invention provides a vitamin K1 injection, comprising vitamin K1, a solubilizer, an amino acid compound, a metal ion chelating agent, an osmotic pressure regulator, a pH regulator, and a solvent.

[0009] As an embodiment of the present invention, the solubilizer includes one or more of polyethylene glycol-12-hydroxystearate and hydroxypropyl β-cyclodextrin; the amino acid compound includes one or more of cysteine, serine, aspartic acid, asparagine, threonine, glutamic acid, glutamine, histidine, lysine, and arginine; the metal ion chelator includes one or more of disodium edetate and sodium citrate; the osmotic pressure regulator includes one or more of sodium chloride and glucose; the pH regulator includes one or more of glacial acetic acid, sodium acetate, hydrochloric acid, sodium hydroxide, phosphoric acid, and sodium dihydrogen phosphate; and the solvent is water for injection.

[0010] As an embodiment of the present invention, the weight ratio of vitamin K1 to solubilizer is 1:2-10, preferably 1:6.

[0011] As an embodiment of the present invention, the weight ratio of vitamin K1 to amino acid compounds is 1:0.5-7, preferably 1:3.

[0012] As an embodiment of the present invention, the weight ratio of the vitamin K1 to the metal ion chelator is 1:0.005-0.2, preferably 1:0.1.

[0013] As an embodiment of the present invention, the composition is composed of the following amounts of raw materials and auxiliary materials: 10 g / L of vitamin K1, 20-100 g / L of solubilizer, 5-70 g / L of amino acid compound, 0.05-2 g / L of metal ion chelator, 0.2-40 g / L of osmotic pressure regulator, and an appropriate amount of pH regulator to adjust the pH to 5.0-7.0.

[0014] As an embodiment of the present invention, the raw materials and auxiliary materials are composed of the following amounts: 10 g / L of vitamin K1, 20-100 g / L of polyethylene glycol-12-hydroxystearate, 5-70 g / L of cysteine, 0.05-2 g / L of disodium edetate, 0.2-40 g / L of glucose, and appropriate amounts of glacial acetic acid and sodium acetate to adjust the pH to 5.0-7.0.

[0015] A second aspect of the present invention provides a method for preparing a vitamin K1 injection, the method comprising the following steps:

[0016] Step 1: Weigh 40-90% of the total solvent into the liquid preparation tank, keep warm and add the prescribed amount of solubilizer, and stir until completely dissolved;

[0017] Step 2: Weigh the prescribed amount of vitamin K1 and place it in a liquid preparation tank, keep warm and stir until it is completely dissolved;

[0018] Step 3: Add the metal ion chelating agent, osmotic pressure regulator and amino acid compound into the liquid preparation tank, keep warm and stir until they are completely dissolved;

[0019] Step 4: adjust the pH to 5.0-7.0 with a pH adjuster at room temperature; add a solvent to the total liquid volume, stir until the mixture is completely mixed, and obtain a drug solution;

[0020] Step 5: Filter and fill the medicinal solution in step 4, and sterilize at high temperature to obtain vitamin K1 injection.

[0021] As an embodiment of the present invention, in step 5, the sterilization parameters of the high temperature sterilization are: 100-130°C, 12-35min, more preferably 121°C, 15min; the temperature range of the insulation in steps 1 to 3 is 25-60°C, and the temperature is kept in the range of 25-60°C during the stirring process to promote dissolution and dispersion, preferably 40°C. As an embodiment of the present invention, the filter membrane selected for the filtration is one of a polyethersulfone (PES) filter membrane, a polytetrafluoroethylene (PTFE) filter membrane or a polyvinylidene fluoride membrane (PVDF) filter membrane.

[0022] Compared with the prior art solutions, the present invention has the following beneficial effects:

[0023] 1. The solubilizer and the amino acid compound are used together in the vitamin K1 injection of the present invention, which is beneficial to improve the tan point of the solubilizer and eliminate the tanning phenomenon during the high-temperature sterilization process. After sterilization, the liquid medicine is clear, and the visible foreign matter and insoluble particles meet the requirements. The solubilizer is polyethylene glycol-12-hydroxystearate, which has higher safety than conventional non-ionic surfactants such as Tween-80, and can improve allergic and anaphylactic reactions such as hypotension, increased heart rate, hemolysis, etc. that may occur during medication.

[0024] 2. The present invention uses an amino acid compound and a metal ion chelator in combination, which is beneficial to reducing the growth rate of related substances (total impurities), ensuring that the quality of the vitamin K1 injection is qualified during the shelf life, and improving the stability of the vitamin K1 injection.

[0025] 3. The present invention is applicable to a variety of terminal sterilization processes, reduces production line environmental requirements, shortens production time, reduces costs, and improves production capacity. DETAILED DESCRIPTION

[0026] The present invention is further described below in conjunction with examples, but the embodiments of the present invention are not limited thereto.

[0027] The raw materials, reagents, materials, and equipment used in the examples can all be purchased through commercial channels. Among them, the vitamin K1 API comes from Nanjing Hanxin Pharmaceutical Technology Co., Ltd.; the No. 2 turbidity solution and the No. 3 turbidity solution are prepared with reference to the 2020 edition of the Chinese Pharmacopoeia General Chapter 0902, and the turbidity standard stock solution comes from Beijing Coast Hongmeng Standard Material Technology Co., Ltd.

[0028] Example 1

[0029] This embodiment provides a vitamin K1 injection and a preparation method thereof, the preparation method comprising the following steps:

[0030] Step 1: weigh 800 g of water for injection into a liquid preparation tank, keep warm to 40°C, add 60 g of polyethylene glycol-12-hydroxystearate, and stir until completely dissolved;

[0031] Step 2: Weigh 10g of vitamin K1 and place it in a liquid preparation tank, keep warm at 40°C and stir until it is completely dissolved;

[0032] Step 3: Add 1g of disodium edetate, 20g of glucose and 30g of cysteine ​​into a liquid preparation tank, and stir at 40°C until completely dissolved;

[0033] Step 4: adjust the pH to 5.0 with sodium acetate and glacial acetic acid at room temperature, add water for injection to make up to 1 L (i.e., make up to the total volume of the solution), stir and mix thoroughly to obtain a drug solution;

[0034] Step 5: Filter the Chinese medicine solution in step 4 continuously through two stages of 0.22 μm PTFE filter membranes, fill with nitrogen, and fill; after filling, sterilize at 121° C. for 15 minutes to obtain vitamin K1 injection.

[0035] Example 2

[0036] This embodiment provides a vitamin K1 injection and a preparation method thereof, the preparation method comprising the following steps:

[0037] Step 1: Weigh 400 g of water for injection into a liquid preparation tank, keep warm at 40°C, add 20 g of hydroxypropyl β-cyclodextrin, and stir until completely dissolved;

[0038] Step 2: Weigh 10g of vitamin K1 and place it in a liquid preparation tank, keep warm at 40°C and stir until it is completely dissolved;

[0039] Step 3: Add 0.05g sodium citrate, 0.2g sodium chloride and 5g histidine into the liquid preparation tank, and stir at 40°C until completely dissolved;

[0040] Step 4: Adjust the pH to 6.0 with hydrochloric acid and sodium hydroxide at room temperature, add water for injection to make up to 1 L (i.e., make up to the total volume of the solution), stir and mix thoroughly to obtain a drug solution;

[0041] Step 5: Filter the Chinese medicine solution in step 4 through 0.45 μm and 0.22 μm PES filter membranes, fill with nitrogen, and fill; after filling, sterilize at 100° C. for 35 minutes to obtain vitamin K1 injection.

[0042] Example 3

[0043] Step 1: weigh 900 g of water for injection into a liquid preparation tank, keep warm to 60°C, add 100 g of polyethylene glycol-12-hydroxystearate, and stir until completely dissolved;

[0044] Step 2: Weigh 10g of vitamin K1 and place it in a liquid preparation tank, keep warm at 60°C and stir until it is completely dissolved;

[0045] Step 3: Add 2g of disodium edetate, 40g of glucose and 70g of arginine into the liquid preparation tank, and stir at 60°C until completely dissolved;

[0046] Step 4: adjust the pH to 7.0 with phosphoric acid and sodium dihydrogen phosphate at room temperature, add water for injection to make up to 1 L (i.e., make up to the total volume of the solution), stir and mix thoroughly to obtain a drug solution;

[0047] Step 5: Filter the Chinese medicine solution in step 4 continuously through two stages of 0.22 μm PVDF filter membranes, fill with nitrogen, and fill; after filling, sterilize at 130° C. for 12 minutes to obtain vitamin K1 injection.

[0048] Example 4

[0049] This embodiment provides a vitamin K1 injection and a preparation method thereof, the preparation method comprising the following steps:

[0050] Step 1: weigh 800 g of water for injection into a liquid preparation tank, keep warm to 25°C, add 50 g of polyethylene glycol-12-hydroxystearate, and stir until completely dissolved;

[0051] Step 2: Weigh 10g of vitamin K1 and place it in a liquid preparation tank, keep warm at 25°C and stir until it is completely dissolved;

[0052] Step 3: Add 1.2g sodium citrate, 1.8g glucose and 30g lysine into the liquid preparation tank, and stir at 25°C to dissolve completely;

[0053] Step 4: adjust the pH to 6.0 with sodium acetate and glacial acetic acid at room temperature, add water for injection to make up to 1 L (i.e., make up to the total volume of the solution), stir and mix thoroughly to obtain a drug solution;

[0054] Step 5: Filter the Chinese medicine solution in step 4 through 0.45 μm and 0.22 μm PVDF filter membranes successively, and fill the solution; after filling, sterilize the solution at 100° C. for 35 min to obtain vitamin K1 injection.

[0055] Example 5

[0056] This embodiment provides a vitamin K1 injection and a preparation method thereof, the preparation method comprising the following steps:

[0057] Step 1: weigh 800 g of water for injection into a liquid preparation tank, keep warm to 40°C, add 60 g of polyethylene glycol-12-hydroxystearate, and stir until completely dissolved;

[0058] Step 2: Weigh 1g of vitamin K1 and place it in a liquid preparation tank, keep warm at 40°C and stir until it is completely dissolved;

[0059] Step 3: Add 1g of disodium edetate, 20g of glucose and 30g of cysteine ​​into a liquid preparation tank, and stir at 40°C until completely dissolved;

[0060] Step 4: adjust the pH to 5.0 with sodium acetate and glacial acetic acid at room temperature, add water for injection to make up to 0.5 L (i.e., make up to the total volume of the solution), stir and mix thoroughly to obtain a drug solution;

[0061] Step 5: Filter the Chinese medicine solution in step 4 continuously through two stages of 0.22 μm PTFE filter membranes, fill with nitrogen, and fill; after filling, sterilize at 121° C. for 15 minutes to obtain vitamin K1 injection.

[0062] Example 6

[0063] This embodiment provides a vitamin K1 injection and a preparation method thereof, the preparation method comprising the following steps:

[0064] Step 1: Weigh 400 g of water for injection into a liquid preparation tank, keep warm at 40°C, add 20 g of hydroxypropyl β-cyclodextrin, and stir until completely dissolved;

[0065] Step 2: Weigh 1g of vitamin K1 and place it in a liquid preparation tank, keep warm at 40°C and stir until it is completely dissolved;

[0066] Step 3: Add 0.05g sodium citrate, 0.2g sodium chloride and 5g histidine into the liquid preparation tank, and stir at 40°C until completely dissolved;

[0067] Step 4: Adjust the pH to 6.0 with hydrochloric acid and sodium hydroxide at room temperature, add water for injection to make up to 0.5 L (i.e., make up to the total volume of the solution), stir and mix thoroughly to obtain a drug solution;

[0068] Step 5: Filter the Chinese medicine solution in step 4 through 0.45 μm and 0.22 μm PES filter membranes, fill with nitrogen, and fill; after filling, sterilize at 100° C. for 35 minutes to obtain vitamin K1 injection.

[0069] Comparative Example 1

[0070] This comparative example provides a vitamin K1 injection and a preparation method thereof, the preparation method comprising the following steps:

[0071] Step 1: weigh 800 g of water for injection into a liquid preparation tank, keep warm to 40°C, add 60 g of polyethylene glycol-12-hydroxystearate, and stir until completely dissolved;

[0072] Step 2: Weigh 10g of vitamin K1 and place it in a liquid preparation tank, keep warm at 40°C and stir until it is completely dissolved;

[0073] Step 3: Add 1g of disodium edetate and 20g of glucose into the liquid preparation tank, and stir at 40°C until completely dissolved;

[0074] Step 4: adjust the pH to 5.0 with sodium acetate and glacial acetic acid at room temperature, add water for injection to make up to 1 L (i.e., make up to the total volume of the solution), stir and mix thoroughly to obtain a drug solution;

[0075] Step 5: Filter the Chinese medicine solution in step 4 continuously through two stages of 0.22 μm PTFE filter membranes, fill with nitrogen, and fill; after filling, sterilize at 121° C. for 15 minutes to obtain vitamin K1 injection.

[0076] Comparative Example 2

[0077] This comparative example provides a vitamin K1 injection and a preparation method thereof, the preparation method comprising the following steps:

[0078] Step 1: weigh 800 g of water for injection into a liquid preparation tank, keep warm to 40°C, add 60 g of polyethylene glycol-12-hydroxystearate, and stir until completely dissolved;

[0079] Step 2: Weigh 10g of vitamin K1 and place it in a liquid preparation tank, keep warm at 40°C and stir until it is completely dissolved;

[0080] Step 3: Add 20g glucose and 30g cysteine ​​into the liquid preparation tank, and stir at 40°C until completely dissolved;

[0081] Step 4: adjust the pH to 5.0 with sodium acetate and glacial acetic acid at room temperature, add water for injection to make up to 1 L (i.e., make up to the total volume of the solution), stir and mix thoroughly to obtain a drug solution;

[0082] Step 5: Filter the Chinese medicine solution in step 4 continuously through two stages of 0.22 μm PTFE filter membranes, fill with nitrogen, and fill; after filling, sterilize at 121° C. for 15 minutes to obtain vitamin K1 injection.

[0083] Comparative Example 3

[0084] This comparative example provides a vitamin K1 injection and a preparation method thereof, the preparation method comprising the following steps:

[0085] Step 1: weigh 800 g of water for injection into a liquid preparation tank, keep warm to 40°C, add 60 g of polysorbate 80, and stir until completely dissolved;

[0086] Step 2: Weigh 10g of vitamin K1 and place it in a liquid preparation tank, keep warm at 40°C and stir until it is completely dissolved;

[0087] Step 3: Add 1g of disodium edetate and 20g of glucose into the liquid preparation tank, and stir at 40°C until completely dissolved;

[0088] Step 4: adjust the pH to 5.0 with sodium acetate or glacial acetic acid, add water for injection to make up to 1 L (i.e., make up to the total volume of the solution), stir and mix thoroughly to obtain a drug solution;

[0089] Step 5: Filter the Chinese medicine solution in step 4 continuously through two stages of 0.22 μm PTFE filter membranes, fill with nitrogen, and fill; after filling, sterilize at 121° C. for 15 minutes to obtain vitamin K1 injection.

[0090] The product quality of the vitamin K1 injection obtained in Example 1-6 and Comparative Example 1-3 after sterilization and during the stability test is shown in Table 1-4.

[0091] Inspection of drug solution quality after sterilization

[0092] Table 1 shows the product quality inspection of vitamin K1 injection before and after sterilization

[0093]

[0094] *The corresponding data are the test results of the vitamin K1 injection sample after it was left to stand for 120 hours and gradually re-dissolved.

[0095] According to Table 1, Examples 1 to 6 are vitamin K1 injections prepared according to the present application. They do not produce blistering during the sterilization process. After sterilization, the liquid is a yellow clear liquid, and the visible foreign matter and insoluble particles meet the requirements, and the total impurities do not change. However, no amino acid compounds are added during the preparation of Comparative Examples 1 and 3. The liquid is stratified and blistering after sterilization. The visible foreign matter after sterilization is unqualified. It needs to be left to stand for at least 120 hours before preliminary redissolution, but the level of insoluble particles after preliminary redissolution is significantly high. In addition, the total impurities of Comparative Examples 1, Comparative Example 2 (without metal ion chelating agent) and Comparative Example 3 after sterilization are higher than those before sterilization, and are higher than those of the example samples.

[0096] It can be seen that the combined use of solubilizers and amino acid compounds is conducive to improving the tanning point of polyethylene glycol-12-hydroxystearate, eliminating the tanning phenomenon during high-temperature sterilization, and the drug solution is clear after sterilization. The combined use of amino acid compounds and metal ion chelators is conducive to reducing the growth rate of related substances (total impurities), thereby improving the stability of vitamin K1 injection.

[0097] Accelerated stability test

[0098] The vitamin K1 injections obtained in Examples 1-6 and Comparative Examples 1-3 were placed under accelerated conditions (temperature 40±2° C., humidity 70±5%) for 6 months. The product quality is shown in Table 2.

[0099] Table 2 shows the accelerated stability study of vitamin K1 injection

[0100]

[0101] The vitamin K1 injection prepared in Examples 1-6 was a yellow clear liquid during the accelerated stability period of 6 months, and the level of insoluble particles was maintained at a low level. The visible foreign matter was qualified; the clarity of Comparative Examples 1 and 3 decreased during the accelerated stability period, and the level of insoluble particles increased. Oil droplets precipitated when accelerated for 6 months, and the visible foreign matter was unqualified. The total impurities of Comparative Examples 1-3 during the stability period were significantly higher than those of the embodiments, and the total impurity limit of vitamin K1 injection in the 2020 edition of the Chinese Pharmacopoeia was exceeded in 6 months (the total impurity limit of vitamin K1 injection in the 2020 edition of the Chinese Pharmacopoeia is 2%). The quality of the comparative examples is inferior to that of the vitamin K1 injection of the present application.

[0102] Long-term stability study

[0103] The vitamin K1 injections obtained in Examples 1-6 and Comparative Examples 1-3 were placed under long-term conditions (temperature 25±2°C, humidity 60±5%) for 24 months. The quality of the obtained products is shown in Table 3.

[0104] Table 3 shows the long-term stability of vitamin K1 injection

[0105]

[0106] According to Table 3, the properties and insoluble particle levels of the vitamin K1 injection prepared according to the present application did not change significantly during the long-term stability test, and the visible foreign matter met the requirements, and the total impurity level was significantly lower than that of the comparative example. During the accelerated stability period of comparative example 1 and comparative example 3, the clarity decreased, the insoluble particle level increased, and oil droplets precipitated during the accelerated 6 months, and the visible foreign matter was unqualified. The total impurities of comparative examples 1-3 during the long-term stability test were significantly higher than those of the embodiments, and the quality of the comparative examples was not as good as that of the vitamin K1 injection of the present application.

[0107] Safety inspection

[0108] The hemolytic properties of the vitamin K1 injections obtained in Examples 1-2, Example 5, and Comparative Example 3 and the histamine levels in dog serum after intravenous injection were investigated. The results are shown in Table 4.

[0109] Table 4 Human erythrocyte hemolytic activity of the obtained vitamin K1 injection and serum histamine level of dogs after intravenous injection

[0110] NO. Hemolytic activity (% lysis of red blood cells) Serum histamine level (nmol) Example 1 2 186 Example 2 4 156 Example 5 4 162 Comparative Example 3 40 79235

[0111] In Example 1 and Example 2, the solubilizers used polyethylene glycol-12-hydroxystearate and hydroxypropyl β-cyclodextrin, respectively, in Example 5, the solubilizer used polyethylene glycol-12-hydroxystearate, and in Comparative Example 3, the solubilizer used polysorbate-80. The hemolytic activity and serum histamine level of the comparative example in Table 4 are significantly higher than those of the examples, which shows that polyethylene glycol-12-hydroxystearate and hydroxypropyl β-cyclodextrin have higher safety and can improve allergic and anaphylactic reactions such as decreased blood pressure, increased heart rate, and hemolysis that may occur during medication.

Claims

1. A vitamin K1 injection, characterized in that: It includes vitamin K1, solubilizer, amino acid compound, metal ion chelator, osmotic pressure regulator, pH regulator and solvent.

2. A vitamin K1 injection according to claim 1, characterized in that: The solubilizer includes one or more of polyethylene glycol-12-hydroxystearate and hydroxypropyl beta-cyclodextrin; the amino acid compound includes one or more of cysteine, serine, aspartic acid, asparagine, threonine, glutamic acid, glutamine, histidine, lysine, and arginine; the metal ion chelator includes one or more of disodium edetate and sodium citrate; the osmotic pressure regulator includes one or more of sodium chloride and glucose; the pH regulator includes one or more of glacial acetic acid, sodium acetate, hydrochloric acid, sodium hydroxide, phosphoric acid, and sodium dihydrogen phosphate; and the solvent is water for injection.

3. A vitamin K1 injection according to claim 2, characterized in that: The weight ratio of the vitamin K1 to the solubilizer is 1:2-10, preferably 1:

6.

4. A vitamin K1 injection according to claim 3, characterized in that: The weight ratio of the vitamin K1 to the amino acid compound is 1:0.5-7, preferably 1:

3.

5. A vitamin K1 injection according to claim 4, characterized in that: The weight ratio of the vitamin K1 to the metal ion chelating agent is 1:0.005-0.2, preferably 1:0.

1.

6. A vitamin K1 injection according to claim 5, characterized in that: The invention is composed of the following raw materials and auxiliary materials: 10 g / L of the vitamin K1, 20-100 g / L of a solubilizer, 5-70 g / L of an amino acid compound, 0.05-2 g / L of a metal ion chelating agent, 0.2-40 g / L of an osmotic pressure regulator, and an appropriate amount of a pH regulator to adjust the pH to 5.0-7.

0.

7. A vitamin K1 injection according to claim 6, characterized in that: The invention is composed of the following raw materials and auxiliary materials: 10 g / L of vitamin K1, 20-100 g / L of polyethylene glycol-12-hydroxystearate, 5-70 g / L of cysteine, 0.05-2 g / L of disodium edetate, 0.2-40 g / L of glucose, and appropriate amounts of glacial acetic acid and sodium acetate to adjust the pH value to 5.0-7.

0.

8. A method for preparing the vitamin K1 injection according to any one of claims 1 to 7, characterized in that: The preparation method comprises the following steps: Step 1: Weigh 40-90% of the total solvent into the liquid preparation tank, keep warm and add the prescribed amount of solubilizer, and stir until completely dissolved; Step 2: Weigh the prescribed amount of vitamin K1 and place it in a liquid preparation tank, keep warm and stir until it is completely dissolved; Step 3: Add the metal ion chelating agent, osmotic pressure regulator and amino acid compound into the liquid preparation tank, keep warm and stir until they are completely dissolved; Step 4: adjust the pH to 5.0-7.0 with a pH adjuster at room temperature; add a solvent to the total liquid volume, stir until the mixture is completely mixed, and obtain a drug solution; Step 5: Filter and fill the medicinal solution in step 4, and sterilize at high temperature to obtain vitamin K1 injection.

9. The method according to claim 8, characterized in that: The filter membrane used for the filtration is at least one of a PES filter membrane, a PTFE filter membrane or a PVDF filter membrane; the insulation temperature range in steps one to three is 25 to 60° C., preferably 40° C.

10. The method according to claim 9, characterized in that: In the step 5, the sterilization parameters of the high temperature sterilization are: 100-130° C., 12-35 min, preferably 121° C., 15 min.

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