Fat-soluble vitamin injection and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, and discloses a fat-soluble vitamin injection and a preparation method thereof. The preparation method comprises the following steps: uniformly mixing soybean oil, vitamin E and lecithin, adding other fat-soluble vitamins, and uniformly mixing under the protection of inert gas; the invention provides a method for preparing the fat-soluble vitamin injection through one-time emulsion formation and a conventional sterilization process by controlling the dissolved oxygen in water for injection and the residual oxygen level of the headspace of an ampoule bottle. The stability of the fat-soluble vitamin injection prepared by the method is obviously improved, and the fat-soluble vitamin injection can be stably stored at 25 DEG C, and has practical significance and important social value.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical preparations, and specifically discloses a fat-soluble vitamin injection and a preparation method thereof. Background Art

[0002] Fat-soluble vitamins include A, D, E, and K, and are commonly used drugs for the treatment of diseases. Fat-soluble vitamin injections are widely used in clinical practice because of the convenience and speed of injection. However, as we all know, fat-soluble vitamins are unstable and are mostly sensitive to light, moisture, heat, and oxygen, requiring high preparation technology, otherwise it is difficult to ensure product quality.

[0003] In the prior art, in order to improve the stability of fat-soluble vitamin injections, the following methods are mainly used for preparation: (1) Preparation by colostrum method: The colostrum system can effectively encapsulate fat-soluble vitamins in tiny oil droplets to protect them from the influence of external environmental factors; (2) Adding metal chelators: Metal chelators can combine with trace metal ions (such as iron ions, copper ions, etc.) in the injection to form stable chelates, thereby preventing the metal ions from catalyzing the oxidation of fat-soluble vitamins and helping to maintain the activity and stability of the vitamins; (3) Sterilization at a temperature slightly lower than 121°C to reduce the storage temperature of the product. However, when prepared by colostrum method, the product is prone to oil floating, resulting in unstable content and seriously affecting product quality; the added metal chelators will also complex the metal elements necessary for the human body, increasing the risk of calcium or other mineral deficiency in the human body; lowering the sterilization temperature may not necessarily ensure the sterility level; lowering the product storage temperature will increase the storage cost. Summary of the invention

[0004] In view of the deficiencies in the prior art, the present invention provides a method for preparing a fat-soluble vitamin injection solution through one-time emulsification and according to conventional sterilization technology by adjusting the addition sequence and controlling the dissolved oxygen in the injection water and the residual oxygen level in the headspace of the ampoule, and provides a complex vitamin injection solution that can be stably stored at 25°C.

[0005] In order to achieve the above-mentioned object of the invention, the present invention adopts the following technical solutions: In a first aspect, the present invention provides a method for preparing a fat-soluble vitamin injection, the preparation method comprising the following steps: Step 1, adding vitamin E and lecithin to soybean oil in sequence, mixing, and then adding other fat-soluble vitamins, mixing under the protection of inert gas, to obtain an oil phase mixture; Step 2: Mix glycerol and water for injection under inert gas protection to obtain a water phase mixture; Step 3, homogenizing and granulating the oil phase mixture and the water phase mixture to obtain a filling liquid; Step 4, filling and sterilizing the filling solution to obtain a fat-soluble vitamin injection solution; Wherein, the dissolved oxygen in the water for injection is ≤200ppb; The other fat-soluble vitamins include vitamin K, vitamin D and vitamin A; During the filling, the oxygen content in the headspace of the ampoule is controlled to be below 2%.

[0006] The present invention provides a method for preparing fat-soluble vitamin injection by one-time emulsification and conventional sterilization process by adjusting the order of adding soybean oil, vitamin E, lecithin and other vitamin raw materials and controlling the dissolved oxygen in the injection water and the residual oxygen level in the headspace of the ampoule. The process flow chart is as follows: Figure 1 As shown. The present invention first dissolves tocopherol and lecithin in soybean oil, utilizes the oxidation difference of lecithin and different types of fat-soluble vitamins, and improves the stability of specific vitamins (such as vitamin A and vitamin D, etc.) in the oil phase dissolution process by adjusting the order of adding raw materials; Compared with the preparation method of conventional fat-soluble vitamin injection, the present invention does not prepare colostrum, but directly mixes the oil phase and the water phase to obtain refined milk in one time, which solves the "floating oil" problem and makes the vitamin content more controllable; In view of the fact that vitamin D in the oil phase is sensitive to dissolved oxygen in water, the present invention improves the stability of vitamin D by controlling the dissolved oxygen in the injection water; The present invention helps to maintain the stability of vitamins (especially vitamin K and vitamin A) during the sterilization process by controlling the residual oxygen content in the headspace of the ampoule. The present invention improves the existing preparation process of fat-soluble vitamin injection by adjusting the order of adding raw materials, controlling the dissolved oxygen in the injection water and the residual oxygen level in the headspace of the ampoule, etc. The improved method does not need to add other expensive equipment on the basis of the original equipment, and has the advantage of being suitable for promotion. In addition, the stability of the fat-soluble vitamin injection product is significantly improved, and it can be stably stored at 25°C, which has practical significance and important social value.

[0007] Preferably, the inert gas includes nitrogen or a rare gas. In the present invention, nitrogen is used as an example for illustration, but a rare gas can also achieve the same effect.

[0008] Preferably, after the homogenization, refined milk is obtained; the droplet size of the refined milk is 250nm~500nm.

[0009] Preferably, the homogenization pressure is 400 Bar~700 Bar.

[0010] Preferably, the sterilization temperature is 121° C. and the time is 8 min to 12 min.

[0011] Preferably, the fat-soluble vitamin injection includes the following components per 1000 mL: vitamin A: 0.12g~0.25g, vitamin K: 0.10g~0.3g, vitamin D: 0.5g~1.5mg, vitamin E: 0.5g~1.5g, soybean oil: 99g~101g, lecithin: 8g~12g, glycerol: 22g~25g, sodium hydroxide: 0.01g~0.02g, and the balance is water for injection.

[0012] Further preferably, the vitamin K includes vitamin K1; The vitamin D includes vitamin D2; The vitamin E includes α-tocopherol.

[0013] The lecithin in the present invention includes soybean lecithin and egg yolk lecithin, which are for injection; vitamin A is added in the form of vitamin A palmitate and is calculated based on the amount converted into vitamin A; vitamin E is added in the form of racemic α-tocopherol; soybean oil is soybean oil for injection; and glycerol is soybean oil for injection.

[0014] In a second aspect, the present invention provides a fat-soluble vitamin injection, which is prepared by the above-mentioned method for preparing the fat-soluble vitamin injection.

[0015] The fat-soluble vitamin injection provided by the present invention can be stored for a long time at room temperature, and under the premise of maintaining a stable vitamin content, the storage cost is reduced, the safety of clinical use is improved, and it has important social significance and economic value. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0017] Figure 1 The present invention is a process flow chart of the preparation method of the fat-soluble vitamin injection.

[0018] Figure 2 This is a liquid phase diagram for the determination of the vitamin E content in Example 1 of the present invention; Figure 3 This is a liquid phase diagram for the determination of the vitamin D2 content in Example 1 of the present invention. DETAILED DESCRIPTION

[0019] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0020] In order to better illustrate the embodiments of the present invention, further examples are given below.

[0021] In the present invention, the methods for determining the contents of vitamin A, vitamin D2 and vitamin K1 are respectively based on the methods recorded in the 2020 edition of the "Chinese Pharmacopoeia" - Vitamin A, Vitamin D2 Injection or Vitamin K1 Injection - Content Determination; the method for determining the content of vitamin E refers to the method recorded in the "Ministry of Chemical Drugs Standard" - Fat-soluble Vitamin Injection (I).

[0022] The contents of different fat-soluble vitamins measured in the present invention are calculated based on the corresponding vitamin content in the prescribed amount as 100%.

[0023] Example 1 1. This embodiment provides a method for preparing a fat-soluble vitamin injection, which is as follows: Step 1: Take 100 g soybean oil, 1.0 g α-tocopherol and 12 g egg yolk lecithin, heat to 70°C and stir for 30 min to dissolve; then add 10.1 g vitamin K, 20.6 mg vitamin D and 0.2 g vitamin A, stir under nitrogen protection, and dissolve evenly at 70°C to obtain oil phase mixture I; Step 2: Take 800 mL of water for injection containing 180 ppb of dissolved oxygen, add 22.5 g of glycerol and 0.01 g of sodium hydroxide, mix well, and protect with nitrogen to obtain aqueous phase mixture I; Step 3, introducing the oil phase mixture I and the water phase mixture I into a homogenizer, homogenizing once at 70°C and 400 Bar pressure to obtain a milky white refined milk with an average milk particle size of 486 nm, then homogenizing the whole particles once, filtering with 5 μm and 1 μm polyethersulfone to obtain filling liquid I; Step 4: Fill the filling solution I and control the residual oxygen in the headspace of the ampoule to ≤1.8%, sterilize at 121° C. for 10 min, and obtain the fat-soluble vitamin injection solution I.

[0024] Second, this example investigates the relevant indicators of the oil phase mixture I, and the specific contents are as follows: The newly prepared oil phase mixture I was sampled and analyzed for α-tocopherol, vitamin K1, vitamin D2, and vitamin A after 15 minutes and 45 minutes respectively. The liquid phase diagram for the determination of vitamin E content is shown in the figure below: Figure 2 As shown, the liquid phase diagram of vitamin D2 content determination is as follows Figure 3 The specific results are shown in Table 1.

[0025] Table 1

[0026] Note: The vitamin content of the prescribed amount is taken as 100%.

[0027] 3. This example also conducted a long-term sample retention study on the fat-soluble vitamin injection solution I at 25°C±2°C and under light-shielding conditions. The results of the vitamin content during the study period are shown in Table 2 below.

[0028] Table 2

[0029] Note: The vitamin content of the prescribed amount is taken as 100%.

[0030] It can be seen from the data in Table 2 that the fat-soluble vitamin injection I prepared in this example was stored at 25°C±2°C. After 24 months of observation, the contents of the four vitamins were all within the range of 98.3% to 102.1%, which was relatively stable.

[0031] Example 2 This embodiment provides a method for preparing a fat-soluble vitamin injection, which is as follows: Step 1: Take 99g soybean oil, 1.5g α-tocopherol and 10g egg yolk lecithin, heat to 75°C and stir for 20min to dissolve; then add 10.2g vitamin K, 21mg vitamin D and 0.12g vitamin A, stir under nitrogen protection, and dissolve evenly at 75°C to obtain oil phase mixture II; Step 2: Take 800 mL of water for injection with a dissolved oxygen content of 120 ppb, add 25 g of glycerol and 0.015 g of sodium hydroxide, mix well, and protect with nitrogen to obtain aqueous phase mixture II; Step 3, introducing the oil phase mixture I and the water phase mixture II into a homogenizer, homogenizing once at 75°C and 600 Bar pressure to obtain a milky white refined milk with an average milk particle size of 304 nm, then homogenizing the whole particles once, filtering with 5 μm and 1 μm polyethersulfone to obtain filling liquid II; Step 4: Fill the filling solution II and control the residual oxygen in the headspace of the ampoule to ≤1.5%, sterilize at 121° C. for 8 min, and obtain the fat-soluble vitamin injection solution II.

[0032] In this embodiment, a long-term sample retention study of fat-soluble vitamin injection II was conducted at 25°C ± 2°C and under light-shielding conditions. The results of the vitamin content during the study period are shown in Table 3 below.

[0033] Table 3

[0034] Note: The vitamin content of the prescribed amount is taken as 100%.

[0035] It can be seen from the data in Table 3 that the fat-soluble vitamin injection II prepared in this example was stored at 25°C±2°C. After 24 months of observation, the contents of the four vitamins were all within the range of 98.2% to 101.1%, which was relatively stable.

[0036] Example 3 This embodiment provides a method for preparing a fat-soluble vitamin injection, which is as follows: Step 1: Take 101 g of soybean oil, 0.5 g of α-tocopherol and 8 g of soybean lecithin, heat to 80°C and stir for 10 min to dissolve; then add 10.3 g of vitamin K, 0.15 mg of vitamin D2 and 0.25 g of vitamin A, stir under nitrogen protection, and dissolve evenly at 80°C to obtain oil phase mixture III; Step 2: Take 800 mL of water for injection with a dissolved oxygen content of 200 ppb, add 22 g of glycerol and 0.02 g of sodium hydroxide, mix well, and protect with nitrogen to obtain aqueous phase mixture III; Step 3, introducing the oil phase mixture III and the water phase mixture III into a homogenizer, homogenizing once at 80°C and 700 Bar pressure to obtain a milky white refined milk with an average milk particle size of 262 nm, then homogenizing the whole particles twice, filtering with 5 μm and 1 μm polyethersulfone to obtain filling liquid III; Step 4: Fill the filling solution III and control the residual oxygen in the headspace of the ampoule to be ≤1.7%, sterilize at 121° C. for 12 min, and obtain the fat-soluble vitamin injection solution III.

[0037] In this embodiment, a long-term sample retention study of the fat-soluble vitamin injection III was conducted at 25°C ± 2°C and under light-shielding conditions. The results of the vitamin content during the study period are shown in Table 4 below.

[0038] Table 4

[0039] Note: The vitamin content of the prescribed amount is taken as 100%.

[0040] It can be seen from the data in Table 4 that the fat-soluble vitamin injection III prepared in this example was stored at 25°C±2°C. After 24 months of observation, the contents of the four vitamins were all within the range of 98.0% to 101.7%, which was relatively stable.

[0041] Comparative Example 1 This comparative example provides a method for preparing a fat-soluble vitamin injection, which is basically the same as that of Example 1, except that the order of adding the raw materials in step 1 is different, as follows: Step 1, take 100g soybean oil and 12g egg yolk lecithin, heat to 70°C and stir for 30min to dissolve; then add 1.0g α-tocopherol, 0.1g vitamin K1, 0.6mg vitamin D2 and 0.2g vitamin A, stir under nitrogen protection, and dissolve evenly at 70°C to obtain oil phase mixture pair I; the parameters of steps 2 to 4 are the same as those in Example 1.

[0042] The newly prepared oil phase mixture was sampled and analyzed for α-tocopherol, vitamin K1, vitamin D2, and vitamin A after 15 minutes and 45 minutes, respectively. The specific results are shown in Table 5.

[0043] Table 5

[0044] Note: The vitamin content of the prescribed amount is taken as 100%.

[0045] Comparative Example 2 This comparative example provides a method for preparing a fat-soluble vitamin injection, which is basically the same as that of Example 1, except that the order of adding the raw materials in step 1 is different, as follows: Step 1, take 100g of soybean oil, heat it to 70°C and stir for 30min to dissolve; then add 12g of egg yolk lecithin, 1.0g of α-tocopherol, 0.1g of vitamin K1, 0.6mg of vitamin D2 and 0.2g of vitamin A, stir under nitrogen protection, and dissolve evenly at 70°C to obtain oil phase mixture pair II; the parameters of steps 2 to 4 are the same as those in Example 1.

[0046] The newly prepared oil phase mixture II was sampled and analyzed for α-tocopherol, vitamin K1, vitamin D2, and vitamin A content after 15 minutes and 45 minutes, and the specific results are shown in Table 6.

[0047] Table 6

[0048] Note: The vitamin content of the prescribed amount is taken as 100%.

[0049] From the comparison of the data in Table 1, Table 5 and Table 6, it can be seen that the order of adding materials in Example 1, the changes in the vitamin contents of the intermediates obtained are significantly better than those in Comparative Examples 1 and 2. The reason may be that soybean oil, tocopherol and lecithin work together to resist oxidation, consume oxygen that may exist in the oil, protect the stability of vitamins, and ensure the stability of the substance.

[0050] Comparative Example 3 This comparative example provides a method for preparing a fat-soluble vitamin injection, which is basically the same as Example 1, except that the dissolved oxygen in the injection water is controlled at 400 ppb in step 2, and the remaining steps and parameters are the same as Example 1. The obtained fat-soluble vitamin injection is recorded as fat-soluble vitamin injection pair III. After measurement, the vitamin D2 content in the obtained fat-soluble vitamin injection pair III is 92.4% (wherein the vitamin D2 content in the prescription amount is 100%).

[0051] Comparative Example 4 This comparative example provides a method for preparing a fat-soluble vitamin injection, which is basically the same as Example 1, except that the dissolved oxygen in the injection water is controlled at 500 ppb in step 2, and the remaining steps and parameters are the same as Example 1. The obtained fat-soluble vitamin injection is recorded as fat-soluble vitamin injection pair IV. After measurement, the vitamin D2 content in the obtained fat-soluble vitamin injection pair IV is 91.6% (wherein the vitamin D2 content in the prescription amount is 100%).

[0052] Comparative Example 5 This comparative example provides a method for preparing a fat-soluble vitamin injection, which is as follows: (1) According to the prescription provided in Example 1 of the present invention, vitamin A, vitamin D2, vitamin E, vitamin K1, soybean oil (for injection), egg yolk lecithin, and glycerol (for injection) are weighed and set aside; (2) Preparation of the aqueous phase: Add about 80% of the total amount of water for injection into a stainless steel tank, and add the prescribed amount of glycerol (for injection) while stirring; (3) Preparation of the oil phase: Add a prescribed amount of soybean oil (for injection) into another stainless steel tank, introduce nitrogen flow, add a prescribed amount of vitamin A, vitamin D2, vitamin E, vitamin K1 and egg yolk lecithin, and stir until the egg yolk lecithin is dissolved; (4) Preparation of colostrum: Add the oil phase slowly into the water phase under high-speed stirring by introducing nitrogen gas, continue stirring at high speed for at least 5 minutes, adjust the pH value of the solution to within the range of 8.0±0.2 with 1M sodium hydroxide solution, and then adjust the volume of colostrum to the theoretical amount and stir evenly; (5) A nitrogen flow is introduced, and the colostrum is homogenized four times at a low pressure of 5 MPa, and then once at a high pressure of 30 MPa, cooled, and then filtered with a 10 μm filter membrane to obtain a filtrate.

[0053] (6) The filtrate is filled into a 10 ml transparent glass ampoule, sealed after filling with nitrogen, and sterilized by moist heat at 118°C for 25 min. After lamp inspection, the fat-soluble vitamin V injection is obtained.

[0054] During the preparation of the fat-soluble vitamin injection for V, it was found that the colostrum prepared in step (4) was unstable. When homogenized for 30 minutes in step (5), trace oil stars were found on the milky white liquid surface with a particle size of 1-3 μm; when homogenized for 60 minutes, a few oil droplets were found on the milky white liquid surface with a particle size of 5-10 μm. According to the method recorded in the comparative document, oil is very easy to float during the production process, and the oil contains vitamins. At the same time, the oil cannot enter the human body, otherwise it will bring great safety hazards. In the preparation method provided in Example 1 of the present invention, after the oil phase and the water phase are directly mixed to form an emulsion at one time, the obtained emulsion droplet particle size is nanometer-level, the distribution range is narrow, and it is more stable and can better control the product quality.

[0055] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing a fat-soluble vitamin injection, characterized in that: The preparation method comprises the following steps: Step 1, adding vitamin E and lecithin to soybean oil in sequence, mixing, and then adding other fat-soluble vitamins, mixing under the protection of inert gas, to obtain an oil phase mixture; Step 2: Under the protection of inert gas, glycerol and water for injection are mixed to obtain an aqueous phase mixture; Step 3, homogenizing and granulating the oil phase mixture and the water phase mixture to obtain a filling liquid; Step 4, filling and sterilizing the filling solution to obtain a fat-soluble vitamin injection solution; Wherein, the dissolved oxygen in the water for injection is ≤200ppb; The other fat-soluble vitamins include vitamin K, vitamin D and vitamin A; During the filling, the oxygen content in the headspace of the ampoule is controlled to be below 2%.

2. The method for preparing the fat-soluble vitamin injection according to claim 1, characterized in that: The inert gas includes any one of nitrogen or a rare gas.

3. The method for preparing the fat-soluble vitamin injection according to claim 1, characterized in that: The particle size of the emulsion droplets after homogenization is 250nm~500nm.

4. The method for preparing the fat-soluble vitamin injection according to claim 1, characterized in that: The homogenization pressure is 400Bar~700Bar.

5. The method for preparing the fat-soluble vitamin injection according to claim 1, characterized in that: The sterilization temperature is 121° C. and the time is 8 min to 12 min.

6. The method for preparing the fat-soluble vitamin injection according to any one of claims 1 to 5, characterized in that: The fat-soluble vitamin injection includes the following components per 1000 mL: vitamin A: 0.12g~0.25g, vitamin K: 0.10g~0.3g, vitamin D: 0.5g~1.5mg, vitamin E: 0.5g~1.5g, soybean oil: 99g~101g, lecithin: 8g~12g, glycerol: 22g~25g, sodium hydroxide: 0.01g~0.02g, and the balance is water for injection.

7. The method for preparing the fat-soluble vitamin injection according to claim 6, characterized in that: The vitamin K comprises vitamin K1; and / or The vitamin D comprises vitamin D2; and / or The vitamin E includes α-tocopherol.

8. A fat-soluble vitamin injection, characterized in that: The fat-soluble vitamin injection is prepared by the preparation method of any one of claims 1 to 7.

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